title: Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis.
abstract: Leber congenital amaurosis (LCA) causes blindness or severe visual impairment at or within a few months of birth. Here we show, using homozygosity mapping, that the LCA5 gene on chromosome 6q14, which encodes the previously unknown ciliary protein lebercilin, is associated with this disease. We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA. In a sixth family, the LCA5 transcript was completely absent. LCA5 is expressed widely throughout development, although the phenotype in affected individuals is limited to the eye. Lebercilin localizes to the connecting cilia of photoreceptors and to the microtubules, centrioles and primary cilia of cultured mammalian cells. Using tandem affinity purification, we identified 24 proteins that link lebercilin to centrosomal and ciliary functions. Members of this interactome represent candidate genes for LCA and other ciliopathies. Our findings emphasize the emerging role of disrupted ciliary processes in the molecular pathogenesis of LCA.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. a.denhollander@antrg.umcn.nl
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Moin D
authors.initials: MD
authors.lastname: Mohamed
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Towns
authors.forename: Tina
authors.initials: T
authors.lastname: Sedmak
authors.forename: Monika
authors.initials: M
authors.lastname: Beer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nagel-Wolfrum
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.forename: Sharola
authors.initials: S
authors.lastname: Dharmaraj
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.forename: Lenka
authors.initials: L
authors.lastname: Ivings
authors.forename: Grange A
authors.initials: GA
authors.lastname: Williams
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.forename: C Geoff
authors.initials: CG
authors.lastname: Woods
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rashid
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Ilse
authors.initials: I
authors.lastname: Gosens
authors.forename: Ferry F J
authors.initials: FF
authors.lastname: Kersten
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Zonneveld
authors.forename: Sylvia E C
authors.initials: SE
authors.lastname: van Beersum
authors.forename: Irene H
authors.initials: IH
authors.lastname: Maumenee
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002923:Cilia / Q000235:genetics; D018389:Codon, Nonsense; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018389:Codon, Nonsense; D005136:Eye Proteins; C522405:LCA5 protein, human; D008869:Microtubule-Associated Proteins