PUBLICATION
Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)
- Authors
- Heon, E., Kim, G., Qin, S., Garrison, J.E., Tavares, E., Vincent, A., Nuangchamnong, N., Scott, C.A., Slusarski, D.C., Sheffield, V.C.
- ID
- ZDB-PUB-160325-8
- Date
- 2016
- Source
- Human molecular genetics 25(11): 2283-2294 (Journal)
- Registered Authors
- Slusarski, Diane C.
- Keywords
- none
- MeSH Terms
-
- Adolescent
- Animals
- Bardet-Biedl Syndrome/genetics*
- Bardet-Biedl Syndrome/pathology
- Disease Models, Animal
- Female
- Genetic Predisposition to Disease*
- Humans
- Kupffer Cells/metabolism
- Kupffer Cells/pathology
- Mutation
- Proteins/genetics*
- Retinal Degeneration/genetics
- Retinal Degeneration/pathology
- Retinal Dystrophies/genetics*
- Retinal Dystrophies/pathology
- Zebrafish/genetics
- PubMed
- 27008867 Full text @ Hum. Mol. Genet.
Citation
Heon, E., Kim, G., Qin, S., Garrison, J.E., Tavares, E., Vincent, A., Nuangchamnong, N., Scott, C.A., Slusarski, D.C., Sheffield, V.C. (2016) Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Human molecular genetics. 25(11):2283-2294.
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*) inC8ORF37, a gene coding for a cilia protein. The proband was overweight (BMI 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, 3 limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus, and elevated liver enzymes. Mutations inC8ORF37were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role ofC8ORF37in a vertebrate system, we performed gene knockdown inDanio rerioand assessed the cardinal features of BBS and visual function. Knockdown ofc8orf37resulted 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 ofC8ORF37mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show thatC8ORF37variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping