A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.

<h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.&...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Fabiola Valenza [verfasserIn] Davide Cittaro [verfasserIn] Elia Stupka [verfasserIn] Donatella Biancolini [verfasserIn] Maria Grazia Patricelli [verfasserIn] Dario Bonanomi [verfasserIn] Dejan Lazarević [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Übergeordnetes Werk:	In: PLoS ONE - Public Library of Science (PLoS), 2007, 14(2019), 1, p e0210097
Übergeordnetes Werk:	volume:14 ; year:2019 ; number:1, p e0210097

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1371/journal.pone.0210097

Katalog-ID:	DOAJ003858820

Internformat


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author_variant	f v fv d c dc e s es d b db m g p mgp d b db d l dl
matchkey_str	article:19326203:2019----::nvlrnaigainogiascaewtclejnsydoe
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publishDate	2019
allfields	10.1371/journal.pone.0210097 doi (DE-627)DOAJ003858820 (DE-599)DOAJ397d8eddb22b4f2eab54369976269c03 DE-627 ger DE-627 rakwb eng Fabiola Valenza verfasserin aut A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling. 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis. Medicine R Science Q Davide Cittaro verfasserin aut Elia Stupka verfasserin aut Donatella Biancolini verfasserin aut Maria Grazia Patricelli verfasserin aut Dario Bonanomi verfasserin aut Dejan Lazarević verfasserin aut In PLoS ONE Public Library of Science (PLoS), 2007 14(2019), 1, p e0210097 (DE-627)523574592 (DE-600)2267670-3 19326203 nnns volume:14 year:2019 number:1, p e0210097 https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/article/397d8eddb22b4f2eab54369976269c03 kostenfrei https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/toc/1932-6203 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2522 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1, p e0210097
spelling	10.1371/journal.pone.0210097 doi (DE-627)DOAJ003858820 (DE-599)DOAJ397d8eddb22b4f2eab54369976269c03 DE-627 ger DE-627 rakwb eng Fabiola Valenza verfasserin aut A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling. 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis. Medicine R Science Q Davide Cittaro verfasserin aut Elia Stupka verfasserin aut Donatella Biancolini verfasserin aut Maria Grazia Patricelli verfasserin aut Dario Bonanomi verfasserin aut Dejan Lazarević verfasserin aut In PLoS ONE Public Library of Science (PLoS), 2007 14(2019), 1, p e0210097 (DE-627)523574592 (DE-600)2267670-3 19326203 nnns volume:14 year:2019 number:1, p e0210097 https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/article/397d8eddb22b4f2eab54369976269c03 kostenfrei https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/toc/1932-6203 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2522 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1, p e0210097
allfields_unstemmed	10.1371/journal.pone.0210097 doi (DE-627)DOAJ003858820 (DE-599)DOAJ397d8eddb22b4f2eab54369976269c03 DE-627 ger DE-627 rakwb eng Fabiola Valenza verfasserin aut A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling. 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis. Medicine R Science Q Davide Cittaro verfasserin aut Elia Stupka verfasserin aut Donatella Biancolini verfasserin aut Maria Grazia Patricelli verfasserin aut Dario Bonanomi verfasserin aut Dejan Lazarević verfasserin aut In PLoS ONE Public Library of Science (PLoS), 2007 14(2019), 1, p e0210097 (DE-627)523574592 (DE-600)2267670-3 19326203 nnns volume:14 year:2019 number:1, p e0210097 https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/article/397d8eddb22b4f2eab54369976269c03 kostenfrei https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/toc/1932-6203 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2522 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1, p e0210097
allfieldsGer	10.1371/journal.pone.0210097 doi (DE-627)DOAJ003858820 (DE-599)DOAJ397d8eddb22b4f2eab54369976269c03 DE-627 ger DE-627 rakwb eng Fabiola Valenza verfasserin aut A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling. 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis. Medicine R Science Q Davide Cittaro verfasserin aut Elia Stupka verfasserin aut Donatella Biancolini verfasserin aut Maria Grazia Patricelli verfasserin aut Dario Bonanomi verfasserin aut Dejan Lazarević verfasserin aut In PLoS ONE Public Library of Science (PLoS), 2007 14(2019), 1, p e0210097 (DE-627)523574592 (DE-600)2267670-3 19326203 nnns volume:14 year:2019 number:1, p e0210097 https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/article/397d8eddb22b4f2eab54369976269c03 kostenfrei https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/toc/1932-6203 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2522 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1, p e0210097
allfieldsSound	10.1371/journal.pone.0210097 doi (DE-627)DOAJ003858820 (DE-599)DOAJ397d8eddb22b4f2eab54369976269c03 DE-627 ger DE-627 rakwb eng Fabiola Valenza verfasserin aut A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling. 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis. Medicine R Science Q Davide Cittaro verfasserin aut Elia Stupka verfasserin aut Donatella Biancolini verfasserin aut Maria Grazia Patricelli verfasserin aut Dario Bonanomi verfasserin aut Dejan Lazarević verfasserin aut In PLoS ONE Public Library of Science (PLoS), 2007 14(2019), 1, p e0210097 (DE-627)523574592 (DE-600)2267670-3 19326203 nnns volume:14 year:2019 number:1, p e0210097 https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/article/397d8eddb22b4f2eab54369976269c03 kostenfrei https://doi.org/10.1371/journal.pone.0210097 kostenfrei https://doaj.org/toc/1932-6203 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_34 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_235 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 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_2522 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2019 1, p e0210097
language	English
source	In PLoS ONE 14(2019), 1, p e0210097 volume:14 year:2019 number:1, p e0210097
sourceStr	In PLoS ONE 14(2019), 1, p e0210097 volume:14 year:2019 number:1, p e0210097
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Medicine R Science Q
isfreeaccess_bool	true
container_title	PLoS ONE
authorswithroles_txt_mv	Fabiola Valenza @@aut@@ Davide Cittaro @@aut@@ Elia Stupka @@aut@@ Donatella Biancolini @@aut@@ Maria Grazia Patricelli @@aut@@ Dario Bonanomi @@aut@@ Dejan Lazarević @@aut@@
publishDateDaySort_date	2019-01-01T00:00:00Z
hierarchy_top_id	523574592
id	DOAJ003858820
language_de	englisch
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author	Fabiola Valenza
spellingShingle	Fabiola Valenza misc Medicine misc R misc Science misc Q A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.
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topic_title	A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling
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title	A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.
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title_full	A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling
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author_browse	Fabiola Valenza Davide Cittaro Elia Stupka Donatella Biancolini Maria Grazia Patricelli Dario Bonanomi Dejan Lazarević
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author-letter	Fabiola Valenza
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title_sort	novel truncating variant of gli2 associated with culler-jones syndrome impairs hedgehog signalling
title_auth	A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.
abstract	<h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.
abstractGer	<h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.
abstract_unstemmed	<h4<Background</h4<GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.<h4<Methods</h4<In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.<h4<Results</h4<Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.<h4<Conclusions</h4<Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.
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title_short	A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.
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A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.

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