Journal article
Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome
Human molecular genetics, Vol.34(13), pp.1108-1122
06/18/2025
DOI: 10.1093/hmg/ddaf058
PMCID: PMC12199350
PMID: 40273360
Abstract
A 29-year-old male presented with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome (BBS). Following negative clinical genetic testing, genome analysis identified biallelic variants in IFT57: p.(Val397Glu) and p.(Lys225Asnfs*17). IFT57 is part of complex B of the intraflagellar transport (IFT) proteins, which is an adaptor to the anterograde transport of proteins, bringing cargo from the base of the primary cilia to the tip. Variants in IFT57 have not yet been associated with BBS or human retinal degeneration, but biallelic splicing variants were associated with a distinct ciliopathy: oral-facial-digital syndrome. Using patient-derived fibroblasts, IFT57-knockouts (KO) of RPE1, and mIMCD3 cells, we showed that p.(Lys225Asnfs*17) is subjected to non-sense mediated decay, and that p.(Val397Glu) is the predominant variant which leads to cilia defects. Exogenous expression of the p.(Val397Glu) variant partially restored structural and functional primary cilia defects, and of the anterograde transport in Ift57-KO mIMCD3 cells but it did not rescue primary cilia in retinal IFT57-KO-RPE1 cells. The cell autonomous effect, likely explains the retinal dystrophy in our proband with BBS.
Details
- Title: Subtitle
- Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome
- Creators
- Alexandra Nitoiu - University of TorontoQihong Zhang - University of IowaErika Tavares - Hospital for Sick ChildrenJanice Min Li - Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children, Toronto, Ontario M5G 0A4, CanadaKashif Ahmed - Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children, Toronto, Ontario M5G 0A4, CanadaKit Green-Sanderson - Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children, Toronto, Ontario M5G 0A4, CanadaMahnoor Rashid - Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children, Toronto, Ontario M5G 0A4, CanadaShahir M Morcos - University of TorontoJayson T Maynes - Program in Molecular Medicine, Peter Gilgan Centre for Research and Learning, 686 Bay Street, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, CanadaEric I Campos - University of TorontoVal C Sheffield - University of IowaAjoy Vincent - University of TorontoElise Héon - University of Toronto
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.34(13), pp.1108-1122
- DOI
- 10.1093/hmg/ddaf058
- PMID
- 40273360
- PMCID
- PMC12199350
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 1460-2083
- eISSN
- 1460-2083
- Publisher
- OXFORD UNIV PRESS
- Grant note
- University of Toronto McLaughlin Centre Whole Genome Sequence Initiative P30EY025580 / NIH HHS The Henry Brent Chair in Innovative Pediatric Ophthalmology Research The Foundation Fighting Blindness Canada FRN 156154 / CIHR The SickKids Ophthalmology Research Fund CD-CMM-0224-0873-HSC / Foundation Fighting Blindness RGPIN-2024-06709 / National Science and Engineering Research Council of Canada
- Language
- English
- Electronic publication date
- 04/24/2025
- Date published
- 06/18/2025
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984816018202771
Metrics
4 Record Views