Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1

Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms g...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Antonia Assunto [verfasserIn] Ursula Ferrara [verfasserIn] Alessandro De Luca [verfasserIn] Claudia Pivonello [verfasserIn] Lisa Lombardo [verfasserIn] Annapina Piscitelli [verfasserIn] Cristina Tortora [verfasserIn] Valentina Pinna [verfasserIn] Paola Daniele [verfasserIn] Rosario Pivonello [verfasserIn] Maria Giovanna Russo [verfasserIn] Giuseppe Limongelli [verfasserIn] Annamaria Colao [verfasserIn] Marco Tartaglia [verfasserIn] Pietro Strisciuglio [verfasserIn] Daniela Melis [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity

Übergeordnetes Werk:	In: Orphanet Journal of Rare Diseases - BMC, 2006, 14(2019), 1, Seite 9
Übergeordnetes Werk:	volume:14 ; year:2019 ; number:1 ; pages:9

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13023-019-1223-1

Katalog-ID:	DOAJ043719120

Internformat


LEADER	01000caa a22002652 4500
001	DOAJ043719120
003	DE-627
005	20230308073730.0
007	cr uuu---uuuuu
008	230227s2019 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.1186/s13023-019-1223-1 \|2 doi
035			\|a (DE-627)DOAJ043719120
035			\|a (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
100	0		\|a Antonia Assunto \|e verfasserin \|4 aut
245	1	0	\|a Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1
264		1	\|c 2019
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
520			\|a Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.
650		4	\|a NF1
650		4	\|a Neurofibromatosis type 1
650		4	\|a Alternative splicing
650		4	\|a Gene expression
650		4	\|a mRNA isoforms
650		4	\|a Phenotypic expressivity
653		0	\|a Medicine
653		0	\|a R
700	0		\|a Ursula Ferrara \|e verfasserin \|4 aut
700	0		\|a Alessandro De Luca \|e verfasserin \|4 aut
700	0		\|a Claudia Pivonello \|e verfasserin \|4 aut
700	0		\|a Lisa Lombardo \|e verfasserin \|4 aut
700	0		\|a Annapina Piscitelli \|e verfasserin \|4 aut
700	0		\|a Cristina Tortora \|e verfasserin \|4 aut
700	0		\|a Valentina Pinna \|e verfasserin \|4 aut
700	0		\|a Paola Daniele \|e verfasserin \|4 aut
700	0		\|a Rosario Pivonello \|e verfasserin \|4 aut
700	0		\|a Maria Giovanna Russo \|e verfasserin \|4 aut
700	0		\|a Giuseppe Limongelli \|e verfasserin \|4 aut
700	0		\|a Annamaria Colao \|e verfasserin \|4 aut
700	0		\|a Marco Tartaglia \|e verfasserin \|4 aut
700	0		\|a Pietro Strisciuglio \|e verfasserin \|4 aut
700	0		\|a Daniela Melis \|e verfasserin \|4 aut
773	0	8	\|i In \|t Orphanet Journal of Rare Diseases \|d BMC, 2006 \|g 14(2019), 1, Seite 9 \|w (DE-627)50900637X \|w (DE-600)2225857-7 \|x 17501172 \|7 nnns
773	1	8	\|g volume:14 \|g year:2019 \|g number:1 \|g pages:9
856	4	0	\|u https://doi.org/10.1186/s13023-019-1223-1 \|z kostenfrei
856	4	0	\|u https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 \|z kostenfrei
856	4	0	\|u http://link.springer.com/article/10.1186/s13023-019-1223-1 \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/1750-1172 \|y Journal toc \|z kostenfrei
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_DOAJ
912			\|a GBV_ILN_11
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_95
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
912			\|a GBV_ILN_2003
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2009
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 14 \|j 2019 \|e 1 \|h 9

Indexfelder

author_variant	a a aa u f uf a d l adl c p cp l l ll a p ap c t ct v p vp p d pd r p rp m g r mgr g l gl a c ac m t mt p s ps d m dm
matchkey_str	article:17501172:2019----::sfrseiin1raeesorltwtdsaeeeiyne
hierarchy_sort_str	2019
publishDate	2019
allfields	10.1186/s13023-019-1223-1 doi (DE-627)DOAJ043719120 (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664 DE-627 ger DE-627 rakwb eng Antonia Assunto verfasserin aut Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1. NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity Medicine R Ursula Ferrara verfasserin aut Alessandro De Luca verfasserin aut Claudia Pivonello verfasserin aut Lisa Lombardo verfasserin aut Annapina Piscitelli verfasserin aut Cristina Tortora verfasserin aut Valentina Pinna verfasserin aut Paola Daniele verfasserin aut Rosario Pivonello verfasserin aut Maria Giovanna Russo verfasserin aut Giuseppe Limongelli verfasserin aut Annamaria Colao verfasserin aut Marco Tartaglia verfasserin aut Pietro Strisciuglio verfasserin aut Daniela Melis verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 14(2019), 1, Seite 9 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:14 year:2019 number:1 pages:9 https://doi.org/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 kostenfrei http://link.springer.com/article/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1 9
spelling	10.1186/s13023-019-1223-1 doi (DE-627)DOAJ043719120 (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664 DE-627 ger DE-627 rakwb eng Antonia Assunto verfasserin aut Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1. NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity Medicine R Ursula Ferrara verfasserin aut Alessandro De Luca verfasserin aut Claudia Pivonello verfasserin aut Lisa Lombardo verfasserin aut Annapina Piscitelli verfasserin aut Cristina Tortora verfasserin aut Valentina Pinna verfasserin aut Paola Daniele verfasserin aut Rosario Pivonello verfasserin aut Maria Giovanna Russo verfasserin aut Giuseppe Limongelli verfasserin aut Annamaria Colao verfasserin aut Marco Tartaglia verfasserin aut Pietro Strisciuglio verfasserin aut Daniela Melis verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 14(2019), 1, Seite 9 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:14 year:2019 number:1 pages:9 https://doi.org/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 kostenfrei http://link.springer.com/article/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1 9
allfields_unstemmed	10.1186/s13023-019-1223-1 doi (DE-627)DOAJ043719120 (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664 DE-627 ger DE-627 rakwb eng Antonia Assunto verfasserin aut Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1. NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity Medicine R Ursula Ferrara verfasserin aut Alessandro De Luca verfasserin aut Claudia Pivonello verfasserin aut Lisa Lombardo verfasserin aut Annapina Piscitelli verfasserin aut Cristina Tortora verfasserin aut Valentina Pinna verfasserin aut Paola Daniele verfasserin aut Rosario Pivonello verfasserin aut Maria Giovanna Russo verfasserin aut Giuseppe Limongelli verfasserin aut Annamaria Colao verfasserin aut Marco Tartaglia verfasserin aut Pietro Strisciuglio verfasserin aut Daniela Melis verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 14(2019), 1, Seite 9 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:14 year:2019 number:1 pages:9 https://doi.org/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 kostenfrei http://link.springer.com/article/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1 9
allfieldsGer	10.1186/s13023-019-1223-1 doi (DE-627)DOAJ043719120 (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664 DE-627 ger DE-627 rakwb eng Antonia Assunto verfasserin aut Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1. NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity Medicine R Ursula Ferrara verfasserin aut Alessandro De Luca verfasserin aut Claudia Pivonello verfasserin aut Lisa Lombardo verfasserin aut Annapina Piscitelli verfasserin aut Cristina Tortora verfasserin aut Valentina Pinna verfasserin aut Paola Daniele verfasserin aut Rosario Pivonello verfasserin aut Maria Giovanna Russo verfasserin aut Giuseppe Limongelli verfasserin aut Annamaria Colao verfasserin aut Marco Tartaglia verfasserin aut Pietro Strisciuglio verfasserin aut Daniela Melis verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 14(2019), 1, Seite 9 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:14 year:2019 number:1 pages:9 https://doi.org/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 kostenfrei http://link.springer.com/article/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1 9
allfieldsSound	10.1186/s13023-019-1223-1 doi (DE-627)DOAJ043719120 (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664 DE-627 ger DE-627 rakwb eng Antonia Assunto verfasserin aut Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1. NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity Medicine R Ursula Ferrara verfasserin aut Alessandro De Luca verfasserin aut Claudia Pivonello verfasserin aut Lisa Lombardo verfasserin aut Annapina Piscitelli verfasserin aut Cristina Tortora verfasserin aut Valentina Pinna verfasserin aut Paola Daniele verfasserin aut Rosario Pivonello verfasserin aut Maria Giovanna Russo verfasserin aut Giuseppe Limongelli verfasserin aut Annamaria Colao verfasserin aut Marco Tartaglia verfasserin aut Pietro Strisciuglio verfasserin aut Daniela Melis verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 14(2019), 1, Seite 9 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:14 year:2019 number:1 pages:9 https://doi.org/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 kostenfrei http://link.springer.com/article/10.1186/s13023-019-1223-1 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1 9
language	English
source	In Orphanet Journal of Rare Diseases 14(2019), 1, Seite 9 volume:14 year:2019 number:1 pages:9
sourceStr	In Orphanet Journal of Rare Diseases 14(2019), 1, Seite 9 volume:14 year:2019 number:1 pages:9
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity Medicine R
isfreeaccess_bool	true
container_title	Orphanet Journal of Rare Diseases
authorswithroles_txt_mv	Antonia Assunto @@aut@@ Ursula Ferrara @@aut@@ Alessandro De Luca @@aut@@ Claudia Pivonello @@aut@@ Lisa Lombardo @@aut@@ Annapina Piscitelli @@aut@@ Cristina Tortora @@aut@@ Valentina Pinna @@aut@@ Paola Daniele @@aut@@ Rosario Pivonello @@aut@@ Maria Giovanna Russo @@aut@@ Giuseppe Limongelli @@aut@@ Annamaria Colao @@aut@@ Marco Tartaglia @@aut@@ Pietro Strisciuglio @@aut@@ Daniela Melis @@aut@@
publishDateDaySort_date	2019-01-01T00:00:00Z
hierarchy_top_id	50900637X
id	DOAJ043719120
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ043719120</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230308073730.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230227s2019 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13023-019-1223-1</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ043719120</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Antonia Assunto</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2019</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">NF1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Neurofibromatosis type 1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Alternative splicing</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene expression</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mRNA isoforms</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Phenotypic expressivity</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Medicine</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">R</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ursula Ferrara</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Alessandro De Luca</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Claudia Pivonello</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Lisa Lombardo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Annapina Piscitelli</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Cristina Tortora</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Valentina Pinna</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Paola Daniele</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Rosario Pivonello</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Maria Giovanna Russo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Giuseppe Limongelli</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Annamaria Colao</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marco Tartaglia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pietro Strisciuglio</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Daniela Melis</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Orphanet Journal of Rare Diseases</subfield><subfield code="d">BMC, 2006</subfield><subfield code="g">14(2019), 1, Seite 9</subfield><subfield code="w">(DE-627)50900637X</subfield><subfield code="w">(DE-600)2225857-7</subfield><subfield code="x">17501172</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:14</subfield><subfield code="g">year:2019</subfield><subfield code="g">number:1</subfield><subfield code="g">pages:9</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1186/s13023-019-1223-1</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">http://link.springer.com/article/10.1186/s13023-019-1223-1</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1750-1172</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">14</subfield><subfield code="j">2019</subfield><subfield code="e">1</subfield><subfield code="h">9</subfield></datafield></record></collection>
author	Antonia Assunto
spellingShingle	Antonia Assunto misc NF1 misc Neurofibromatosis type 1 misc Alternative splicing misc Gene expression misc mRNA isoforms misc Phenotypic expressivity misc Medicine misc R Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1
authorStr	Antonia Assunto
ppnlink_with_tag_str_mv	@@773@@(DE-627)50900637X
format	electronic Article
delete_txt_mv	keep
author_role	aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut
collection	DOAJ
remote_str	true
illustrated	Not Illustrated
issn	17501172
topic_title	Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 NF1 Neurofibromatosis type 1 Alternative splicing Gene expression mRNA isoforms Phenotypic expressivity
topic	misc NF1 misc Neurofibromatosis type 1 misc Alternative splicing misc Gene expression misc mRNA isoforms misc Phenotypic expressivity misc Medicine misc R
topic_unstemmed	misc NF1 misc Neurofibromatosis type 1 misc Alternative splicing misc Gene expression misc mRNA isoforms misc Phenotypic expressivity misc Medicine misc R
topic_browse	misc NF1 misc Neurofibromatosis type 1 misc Alternative splicing misc Gene expression misc mRNA isoforms misc Phenotypic expressivity misc Medicine misc R
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	cr
hierarchy_parent_title	Orphanet Journal of Rare Diseases
hierarchy_parent_id	50900637X
hierarchy_top_title	Orphanet Journal of Rare Diseases
isfreeaccess_txt	true
familylinks_str_mv	(DE-627)50900637X (DE-600)2225857-7
title	Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1
ctrlnum	(DE-627)DOAJ043719120 (DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664
title_full	Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1
author_sort	Antonia Assunto
journal	Orphanet Journal of Rare Diseases
journalStr	Orphanet Journal of Rare Diseases
lang_code	eng
isOA_bool	true
recordtype	marc
publishDateSort	2019
contenttype_str_mv	txt
container_start_page	9
author_browse	Antonia Assunto Ursula Ferrara Alessandro De Luca Claudia Pivonello Lisa Lombardo Annapina Piscitelli Cristina Tortora Valentina Pinna Paola Daniele Rosario Pivonello Maria Giovanna Russo Giuseppe Limongelli Annamaria Colao Marco Tartaglia Pietro Strisciuglio Daniela Melis
container_volume	14
format_se	Elektronische Aufsätze
author-letter	Antonia Assunto
doi_str_mv	10.1186/s13023-019-1223-1
author2-role	verfasserin
title_sort	isoform-specific nf1 mrna levels correlate with disease severity in neurofibromatosis type 1
title_auth	Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1
abstract	Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.
abstractGer	Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.
abstract_unstemmed	Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700
container_issue	1
title_short	Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1
url	https://doi.org/10.1186/s13023-019-1223-1 https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664 http://link.springer.com/article/10.1186/s13023-019-1223-1 https://doaj.org/toc/1750-1172
remote_bool	true
author2	Ursula Ferrara Alessandro De Luca Claudia Pivonello Lisa Lombardo Annapina Piscitelli Cristina Tortora Valentina Pinna Paola Daniele Rosario Pivonello Maria Giovanna Russo Giuseppe Limongelli Annamaria Colao Marco Tartaglia Pietro Strisciuglio Daniela Melis
author2Str	Ursula Ferrara Alessandro De Luca Claudia Pivonello Lisa Lombardo Annapina Piscitelli Cristina Tortora Valentina Pinna Paola Daniele Rosario Pivonello Maria Giovanna Russo Giuseppe Limongelli Annamaria Colao Marco Tartaglia Pietro Strisciuglio Daniela Melis
ppnlink	50900637X
mediatype_str_mv	c
isOA_txt	true
hochschulschrift_bool	false
doi_str	10.1186/s13023-019-1223-1
up_date	2024-07-03T19:06:27.539Z
_version_	1803585939089391616
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ043719120</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230308073730.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230227s2019 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13023-019-1223-1</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ043719120</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ5c639a6a498f4a9192924c7c0741b664</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Antonia Assunto</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2019</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">NF1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Neurofibromatosis type 1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Alternative splicing</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gene expression</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mRNA isoforms</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Phenotypic expressivity</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Medicine</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">R</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ursula Ferrara</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Alessandro De Luca</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Claudia Pivonello</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Lisa Lombardo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Annapina Piscitelli</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Cristina Tortora</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Valentina Pinna</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Paola Daniele</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Rosario Pivonello</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Maria Giovanna Russo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Giuseppe Limongelli</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Annamaria Colao</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marco Tartaglia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pietro Strisciuglio</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Daniela Melis</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Orphanet Journal of Rare Diseases</subfield><subfield code="d">BMC, 2006</subfield><subfield code="g">14(2019), 1, Seite 9</subfield><subfield code="w">(DE-627)50900637X</subfield><subfield code="w">(DE-600)2225857-7</subfield><subfield code="x">17501172</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:14</subfield><subfield code="g">year:2019</subfield><subfield code="g">number:1</subfield><subfield code="g">pages:9</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1186/s13023-019-1223-1</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/5c639a6a498f4a9192924c7c0741b664</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">http://link.springer.com/article/10.1186/s13023-019-1223-1</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1750-1172</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">14</subfield><subfield code="j">2019</subfield><subfield code="e">1</subfield><subfield code="h">9</subfield></datafield></record></collection>
score	7.4027786

Nicht das Richtige dabei?

Schreiben Sie uns!

Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?