Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)

Elise Heon; Gunhee Kim; Sophie Qin; Janelle E Garrison; Erika Tavares; Ajoy Vincent; Nina Nuangchamnong; C Anthony Scott; Diane C Slusarski; Val C Sheffield

doi:10.1093/hmg/ddw096

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Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)

Journal article

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Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)

Elise Heon, Gunhee Kim, Sophie Qin, Janelle E Garrison, Erika Tavares, Ajoy Vincent, Nina Nuangchamnong, C Anthony Scott, Diane C Slusarski and Val C Sheffield

Human molecular genetics, Vol.25(11), pp.2283-2294

06/01/2016

DOI: 10.1093/hmg/ddw096

PMCID: PMC5081059

PMID: 27008867

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Abstract

Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17-year-old female affected with BBS did not identify any mutation in the known BBS genes. Whole-genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) in C8ORF37, a gene coding for a cilia protein. The proband was overweight (body mass index 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, three limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus and elevated liver enzymes. Mutations in C8ORF37 were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role of C8ORF37 in a vertebrate system, we performed gene knockdown in Danio rerio and assessed the cardinal features of BBS and visual function. Knockdown of c8orf37 resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association of C8ORF37 mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show that C8ORF37 variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.

Mutation

Kupffer Cells - pathology

Genetic Predisposition to Disease

Retinal Degeneration - genetics

Humans

Retinal Dystrophies - pathology

Zebrafish - genetics

Proteins - genetics

Animals

Bardet-Biedl Syndrome - pathology

Adolescent

Bardet-Biedl Syndrome - genetics

Female

Kupffer Cells - metabolism

Retinal Degeneration - pathology

Retinal Dystrophies - genetics

Disease Models, Animal

Details

Title: Subtitle: Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)
Creators: Elise Heon - Hospital for Sick Children
Gunhee Kim - Department of Pediatrics, Division of Medical Genetics, Wynn Institute for Vision Research, Carver College of Medicine
Sophie Qin - Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, M5G 1X8 Canada
Janelle E Garrison - Department of Pediatrics, Division of Medical Genetics, Wynn Institute for Vision Research, Carver College of Medicine
Erika Tavares - Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, M5G 1X8 Canada
Ajoy Vincent - Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, M5G 1X8 Canada Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, M5G 1X8 Canada
Nina Nuangchamnong - Department of Obstetrics and Gynecology, Carver College of Medicine
C Anthony Scott - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Diane C Slusarski - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Val C Sheffield - Department of Pediatrics, Division of Medical Genetics, Wynn Institute for Vision Research, Carver College of Medicine
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.25(11), pp.2283-2294
DOI: 10.1093/hmg/ddw096
PMID: 27008867
PMCID: PMC5081059
NLM abbreviation: Hum Mol Genet
ISSN: 1460-2083
eISSN: 1460-2083
Publisher: England
Grant note: R01 EY011298 / NEI NIH HHS R01 NS083543 / NINDS NIH HHS T32 HL007121 / NHLBI NIH HHS R01 EY017168 / NEI NIH HHS
Language: English
Date published: 06/01/2016
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biology; Obstetrics and Gynecology; Ophthalmology and Visual Sciences
Record Identifier: 9983931889902771

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