CRB1 mutation spectrum in inherited retinal dystrophies.
Mutations in the Crumbs homologue 1 (CRB1) gene have been reported in patients with a variety of autosomal recessive retinal dystrophies, including retinitis pigmentosa (RP) with preserved paraarteriolar retinal pigment epithelium (PPRPE), RP with Coats-like exudative vasculopathy, early onset RP without PPRPE, and Leber congenital amaurosis (LCA). We extended our investigations of CRB1 in these retinal dystrophies, and identified nine novel CRB1 sequence variants. In addition, we screened patients with "classic" RP and classic Coats disease (without RP), but no pathologic sequence variants were found in the CRB1 gene. In total, 71 different sequence variants have been identified on 184 CRB1 alleles of patients with retinal dystrophies, including amino acid substitutions, frameshift, nonsense, and splice site mutations, in-frame deletions, and large insertions. Recent studies in two animal models, mouse and Drosophila, and in vivo high-resolution microscopy in patients with LCA, have shed light on the role of CRB1 in the pathogenesis of retinal dystrophies and its function in the photoreceptors. In this article, we provide an overview of the currently known CRB1 sequence variants, predict their effect, and propose a genotype-phenotype correlation model for CRB1 mutations.
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands. a.denhollander@antrg.umcn.nl
Anneke I
AI
den Hollander
Jason
J
Davis
Saskia D
SD
van der Velde-Visser
Marijke N
MN
Zonneveld
Chiara O
CO
Pierrottet
Robert K
RK
Koenekoop
Ulrich
U
Kellner
L Ingeborgh
LI
van den Born
John R
JR
Heckenlively
Carel B
CB
Hoyng
Penny A
PA
Handford
Ronald
R
Roepman
Frans P M
FP
Cremers
D000595:Amino Acid Sequence; D000818:Animals; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology
C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins