A novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen.
OBJECTIVE
The purpose of this study is to identify the genetic defect in a Turkish family with autosomal recessive retinitis pigmentosa, nanophthalmos, and optic disc drusen.


METHODS
Ophthalmological examinations consisted of measuring the best-corrected visual acuity and the refractive error, electroretinography, optical coherence tomography, B-mode ultrasonography, and fundus photography. The involvement of the membrane frizzled-related protein (MFRP) gene in this family was studied with direct DNA sequencing of the coding exons of MFRP and with linkage analysis with microsatellite markers. After MFRP was excluded, genome-wide homozygosity mapping was performed with 250 K single nucleotide polymorphism (SNP) microarrays. Mutation analysis of the crumbs homolog 1 (CRB1) gene was performed with direct sequencing.


RESULTS
Ophthalmological evaluation of both affected individuals in the family revealed a decreased axial length (18-19 mm), retinal dystrophy, macular edema, and hyperopia of >+8.0 diopters. Sequencing of MFRP did not reveal any pathogenic changes, and microsatellite marker analysis showed that the chromosomal region did not segregate within the disease in this family. Genome-wide homozygosity mapping using single nucleotide polymorphism microarrays revealed a 28-Mb homozygous region encompassing the CRB1 gene, and direct sequencing disclosed a novel homozygous missense mutation (p.Gly833Asp) in CRB1.


CONCLUSIONS
Previous studies associated mutations in the MFRP gene with the syndrome nanophthalmos-retinitis pigmentosa-foveoschisis-optic disc drusen. In this study, we demonstrated that a similar disease complex can be caused by mutations in the CRB1 gene.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Codrut C
CC
Paun
Benjamin J
BJ
Pijl
Anna M
AM
Siemiatkowska
Rob W J
RW
Collin
Frans P M
FP
Cremers
Carel B
CB
Hoyng
Anneke I
AI
den Hollander
D000293:Adolescent; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004596:Electroretinography; D005091:Exons; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008850:Microphthalmos / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015594:Optic Disk Drusen / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000150:complications / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D000099274:Frizzled-Related Proteins
D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C448939:CRB1 protein, human; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins