TY - JOUR
T1 - Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies
AU - UK Inherited Retinal Dystrophy Consortium
AU - Xu, Mingchu
AU - Xie, Yajing (Angela)
AU - Abouzeid, Hana
AU - Gordon, Christopher T.
AU - Fiorentino, Alessia
AU - Sun, Zixi
AU - Lehman, Anna
AU - Osman, Ihab S.
AU - Dharmat, Rachayata
AU - Riveiro-Alvarez, Rosa
AU - Bapst-Wicht, Linda
AU - Babino, Darwin
AU - Arno, Gavin
AU - Busetto, Virginia
AU - Zhao, Li
AU - Li, Hui
AU - Lopez-Martinez, Miguel A.
AU - Azevedo, Liliana F.
AU - Hubert, Laurence
AU - Pontikos, Nikolas
AU - Eblimit, Aiden
AU - Lorda-Sanchez, Isabel
AU - Kheir, Valeria
AU - Plagnol, Vincent
AU - Oufadem, Myriam
AU - Soens, Zachry T.
AU - Yang, Lizhu
AU - Bole-Feysot, Christine
AU - Pfundt, Rolph
AU - Allaman-Pillet, Nathalie
AU - Nitschké, Patrick
AU - Cheetham, Michael E.
AU - Lyonnet, Stanislas
AU - Agrawal, Smriti A.
AU - Li, Huajin
AU - Pinton, Gaëtan
AU - Michaelides, Michel
AU - Besmond, Claude
AU - Li, Yumei
AU - Yuan, Zhisheng
AU - von Lintig, Johannes
AU - Webster, Andrew R.
AU - Le Hir, Hervé
AU - Stoilov, Peter
AU - Black, Graeme
AU - Hall, Georgina
AU - Gillespie, Rachel
AU - Ramsden, Simon
AU - Manson, Forbes
AU - Sergouniotis, Panagiotis
N1 - Publisher Copyright:
© 2017 American Society of Human Genetics
PY - 2017/4/6
Y1 - 2017/4/6
N2 - Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.
AB - Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.
KW - brachydachtyly
KW - craniofacial defects
KW - CRISPR-Cas9
KW - CWC27
KW - neurological defects
KW - retinal degeneration
KW - short stature
KW - spliceosome
KW - syndrome
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U2 - 10.1016/j.ajhg.2017.02.008
DO - 10.1016/j.ajhg.2017.02.008
M3 - Article
C2 - 28285769
AN - SCOPUS:85014584653
SN - 0002-9297
VL - 100
SP - 592
EP - 604
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -