Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease

Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16%...
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Autor*in:	Caciotti, Anna [verfasserIn] Tonin, Rodolfo Mort, Matthew Cooper, David N. Gasperini, Serena Rigoldi, Miriam Parini, Rossella Deodato, Federica Taurisano, Roberta Sibilio, Michelina Parenti, Giancarlo Guerrini, Renzo Morrone, Amelia

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	GALNS Morquio a disease Mucopolysaccharidosis IVA Deep intronic mutations mRNA defects Whole gene sequencing

Anmerkung:	© The Author(s). 2018

Übergeordnetes Werk:	Enthalten in: BMC medical genetics - London : BioMed Central, 2000, 19(2018), 1 vom: 11. Okt.
Übergeordnetes Werk:	volume:19 ; year:2018 ; number:1 ; day:11 ; month:10

Links:	Volltext

DOI / URN:	10.1186/s12881-018-0694-6

Katalog-ID:	SPR027500144

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520			\|a Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease.
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allfields	10.1186/s12881-018-0694-6 doi (DE-627)SPR027500144 (SPR)s12881-018-0694-6-e DE-627 ger DE-627 rakwb eng Caciotti, Anna verfasserin aut Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. GALNS (dpeaa)DE-He213 Morquio a disease (dpeaa)DE-He213 Mucopolysaccharidosis IVA (dpeaa)DE-He213 Deep intronic mutations (dpeaa)DE-He213 mRNA defects (dpeaa)DE-He213 Whole gene sequencing (dpeaa)DE-He213 Tonin, Rodolfo aut Mort, Matthew aut Cooper, David N. aut Gasperini, Serena aut Rigoldi, Miriam aut Parini, Rossella aut Deodato, Federica aut Taurisano, Roberta aut Sibilio, Michelina aut Parenti, Giancarlo aut Guerrini, Renzo aut Morrone, Amelia (orcid)0000-0003-2890-8179 aut Enthalten in BMC medical genetics London : BioMed Central, 2000 19(2018), 1 vom: 11. Okt. (DE-627)326643788 (DE-600)2041359-2 1471-2350 nnns volume:19 year:2018 number:1 day:11 month:10 https://dx.doi.org/10.1186/s12881-018-0694-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 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 19 2018 1 11 10
spelling	10.1186/s12881-018-0694-6 doi (DE-627)SPR027500144 (SPR)s12881-018-0694-6-e DE-627 ger DE-627 rakwb eng Caciotti, Anna verfasserin aut Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. GALNS (dpeaa)DE-He213 Morquio a disease (dpeaa)DE-He213 Mucopolysaccharidosis IVA (dpeaa)DE-He213 Deep intronic mutations (dpeaa)DE-He213 mRNA defects (dpeaa)DE-He213 Whole gene sequencing (dpeaa)DE-He213 Tonin, Rodolfo aut Mort, Matthew aut Cooper, David N. aut Gasperini, Serena aut Rigoldi, Miriam aut Parini, Rossella aut Deodato, Federica aut Taurisano, Roberta aut Sibilio, Michelina aut Parenti, Giancarlo aut Guerrini, Renzo aut Morrone, Amelia (orcid)0000-0003-2890-8179 aut Enthalten in BMC medical genetics London : BioMed Central, 2000 19(2018), 1 vom: 11. Okt. (DE-627)326643788 (DE-600)2041359-2 1471-2350 nnns volume:19 year:2018 number:1 day:11 month:10 https://dx.doi.org/10.1186/s12881-018-0694-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 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 19 2018 1 11 10
allfields_unstemmed	10.1186/s12881-018-0694-6 doi (DE-627)SPR027500144 (SPR)s12881-018-0694-6-e DE-627 ger DE-627 rakwb eng Caciotti, Anna verfasserin aut Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. GALNS (dpeaa)DE-He213 Morquio a disease (dpeaa)DE-He213 Mucopolysaccharidosis IVA (dpeaa)DE-He213 Deep intronic mutations (dpeaa)DE-He213 mRNA defects (dpeaa)DE-He213 Whole gene sequencing (dpeaa)DE-He213 Tonin, Rodolfo aut Mort, Matthew aut Cooper, David N. aut Gasperini, Serena aut Rigoldi, Miriam aut Parini, Rossella aut Deodato, Federica aut Taurisano, Roberta aut Sibilio, Michelina aut Parenti, Giancarlo aut Guerrini, Renzo aut Morrone, Amelia (orcid)0000-0003-2890-8179 aut Enthalten in BMC medical genetics London : BioMed Central, 2000 19(2018), 1 vom: 11. Okt. (DE-627)326643788 (DE-600)2041359-2 1471-2350 nnns volume:19 year:2018 number:1 day:11 month:10 https://dx.doi.org/10.1186/s12881-018-0694-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 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 19 2018 1 11 10
allfieldsGer	10.1186/s12881-018-0694-6 doi (DE-627)SPR027500144 (SPR)s12881-018-0694-6-e DE-627 ger DE-627 rakwb eng Caciotti, Anna verfasserin aut Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. GALNS (dpeaa)DE-He213 Morquio a disease (dpeaa)DE-He213 Mucopolysaccharidosis IVA (dpeaa)DE-He213 Deep intronic mutations (dpeaa)DE-He213 mRNA defects (dpeaa)DE-He213 Whole gene sequencing (dpeaa)DE-He213 Tonin, Rodolfo aut Mort, Matthew aut Cooper, David N. aut Gasperini, Serena aut Rigoldi, Miriam aut Parini, Rossella aut Deodato, Federica aut Taurisano, Roberta aut Sibilio, Michelina aut Parenti, Giancarlo aut Guerrini, Renzo aut Morrone, Amelia (orcid)0000-0003-2890-8179 aut Enthalten in BMC medical genetics London : BioMed Central, 2000 19(2018), 1 vom: 11. Okt. (DE-627)326643788 (DE-600)2041359-2 1471-2350 nnns volume:19 year:2018 number:1 day:11 month:10 https://dx.doi.org/10.1186/s12881-018-0694-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 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 19 2018 1 11 10
allfieldsSound	10.1186/s12881-018-0694-6 doi (DE-627)SPR027500144 (SPR)s12881-018-0694-6-e DE-627 ger DE-627 rakwb eng Caciotti, Anna verfasserin aut Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. GALNS (dpeaa)DE-He213 Morquio a disease (dpeaa)DE-He213 Mucopolysaccharidosis IVA (dpeaa)DE-He213 Deep intronic mutations (dpeaa)DE-He213 mRNA defects (dpeaa)DE-He213 Whole gene sequencing (dpeaa)DE-He213 Tonin, Rodolfo aut Mort, Matthew aut Cooper, David N. aut Gasperini, Serena aut Rigoldi, Miriam aut Parini, Rossella aut Deodato, Federica aut Taurisano, Roberta aut Sibilio, Michelina aut Parenti, Giancarlo aut Guerrini, Renzo aut Morrone, Amelia (orcid)0000-0003-2890-8179 aut Enthalten in BMC medical genetics London : BioMed Central, 2000 19(2018), 1 vom: 11. Okt. (DE-627)326643788 (DE-600)2041359-2 1471-2350 nnns volume:19 year:2018 number:1 day:11 month:10 https://dx.doi.org/10.1186/s12881-018-0694-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 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 19 2018 1 11 10
language	English
source	Enthalten in BMC medical genetics 19(2018), 1 vom: 11. Okt. volume:19 year:2018 number:1 day:11 month:10
sourceStr	Enthalten in BMC medical genetics 19(2018), 1 vom: 11. Okt. volume:19 year:2018 number:1 day:11 month:10
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	GALNS Morquio a disease Mucopolysaccharidosis IVA Deep intronic mutations mRNA defects Whole gene sequencing
isfreeaccess_bool	true
container_title	BMC medical genetics
authorswithroles_txt_mv	Caciotti, Anna @@aut@@ Tonin, Rodolfo @@aut@@ Mort, Matthew @@aut@@ Cooper, David N. @@aut@@ Gasperini, Serena @@aut@@ Rigoldi, Miriam @@aut@@ Parini, Rossella @@aut@@ Deodato, Federica @@aut@@ Taurisano, Roberta @@aut@@ Sibilio, Michelina @@aut@@ Parenti, Giancarlo @@aut@@ Guerrini, Renzo @@aut@@ Morrone, Amelia @@aut@@
publishDateDaySort_date	2018-10-11T00:00:00Z
hierarchy_top_id	326643788
id	SPR027500144
language_de	englisch
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Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. 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author	Caciotti, Anna
spellingShingle	Caciotti, Anna misc GALNS misc Morquio a disease misc Mucopolysaccharidosis IVA misc Deep intronic mutations misc mRNA defects misc Whole gene sequencing Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
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topic_title	Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease GALNS (dpeaa)DE-He213 Morquio a disease (dpeaa)DE-He213 Mucopolysaccharidosis IVA (dpeaa)DE-He213 Deep intronic mutations (dpeaa)DE-He213 mRNA defects (dpeaa)DE-He213 Whole gene sequencing (dpeaa)DE-He213
topic	misc GALNS misc Morquio a disease misc Mucopolysaccharidosis IVA misc Deep intronic mutations misc mRNA defects misc Whole gene sequencing
topic_unstemmed	misc GALNS misc Morquio a disease misc Mucopolysaccharidosis IVA misc Deep intronic mutations misc mRNA defects misc Whole gene sequencing
topic_browse	misc GALNS misc Morquio a disease misc Mucopolysaccharidosis IVA misc Deep intronic mutations misc mRNA defects misc Whole gene sequencing
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title	Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
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title_full	Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
author_sort	Caciotti, Anna
journal	BMC medical genetics
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author_browse	Caciotti, Anna Tonin, Rodolfo Mort, Matthew Cooper, David N. Gasperini, Serena Rigoldi, Miriam Parini, Rossella Deodato, Federica Taurisano, Roberta Sibilio, Michelina Parenti, Giancarlo Guerrini, Renzo Morrone, Amelia
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author-letter	Caciotti, Anna
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title_sort	mis-splicing of the galns gene resulting from deep intronic mutations as a cause of morquio a disease
title_auth	Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
abstract	Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. © The Author(s). 2018
abstractGer	Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. © The Author(s). 2018
abstract_unstemmed	Background Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients. Methods In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients. Results Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery. Conclusions We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease. © The Author(s). 2018
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title_short	Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
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author2	Tonin, Rodolfo Mort, Matthew Cooper, David N. Gasperini, Serena Rigoldi, Miriam Parini, Rossella Deodato, Federica Taurisano, Roberta Sibilio, Michelina Parenti, Giancarlo Guerrini, Renzo Morrone, Amelia
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Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease

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