title: Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).
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.
authors.affiliation: 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 Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, M5G 1X8 Canada elise.heon@sickkids.ca.
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Wynn Institute for Vision Research, Carver College of Medicine.
authors.forename: Gunhee
authors.initials: G
authors.lastname: Kim
authors.affiliation: Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, M5G 1X8 Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Qin
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Wynn Institute for Vision Research, Carver College of Medicine.
authors.forename: Janelle E
authors.initials: JE
authors.lastname: Garrison
authors.affiliation: Program of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, M5G 1X8 Canada.
authors.forename: Erika
authors.initials: E
authors.lastname: Tavares
authors.affiliation: 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.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Department of Obstetrics and Gynecology, Carver College of Medicine.
authors.forename: Nina
authors.initials: N
authors.lastname: Nuangchamnong
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Scott
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Slusarski
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Wynn Institute for Vision Research, Carver College of Medicine.
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
mesh_terms: D000293:Adolescent; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology; D058499:Retinal Dystrophies / Q000235:genetics* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics
chemical_list: D011506:Proteins; C570604:CFAP418 protein, human