Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis.
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.
den Hollander
Anneke I
AI
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. a.denhollander@antrg.umcn.nl
Koenekoop
Robert K
RK
Mohamed
Moin D
MD
Arts
Heleen H
HH
Boldt
Karsten
K
Towns
Katherine V
KV
Sedmak
Tina
T
Beer
Monika
M
Nagel-Wolfrum
Kerstin
K
McKibbin
Martin
M
Dharmaraj
Sharola
S
Lopez
Irma
I
Ivings
Lenka
L
Williams
Grange A
GA
Springell
Kelly
K
Woods
C Geoff
CG
Jafri
Hussain
H
Rashid
Yasmin
Y
Strom
Tim M
TM
van der Zwaag
Bert
B
Gosens
Ilse
I
Kersten
Ferry F J
FF
van Wijk
Erwin
E
Veltman
Joris A
JA
Zonneveld
Marijke N
MN
van Beersum
Sylvia E C
SE
Maumenee
Irene H
IH
Wolfrum
Uwe
U
Cheetham
Michael E
ME
Ueffing
Marius
M
Cremers
Frans P M
FP
Inglehearn
Chris F
CF
Roepman
Ronald
R
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
D018389:Codon, Nonsense; D005136:Eye Proteins; C522405:LCA5 protein, human; D008869:Microtubule-Associated Proteins