title: Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement.
abstract: Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166(∗)]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Estrada-Cuzcano
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Ygal
authors.initials: Y
authors.lastname: Rotenstreich
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Tzipora C
authors.initials: TC
authors.lastname: Falik-Zaccai
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hipp
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Stef J F
authors.initials: SJ
authors.lastname: Letteboer
authors.forename: Dorus A
authors.initials: DA
authors.lastname: Mans
authors.forename: Ellen A W
authors.initials: EA
authors.lastname: Blokland
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kwint
authors.forename: Sabine J
authors.initials: SJ
authors.lastname: Gijsen
authors.forename: Ramon A C
authors.initials: RA
authors.lastname: van Huet
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: B Jeroen
authors.initials: BJ
authors.lastname: Klevering
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D058499:Retinal Dystrophies / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000378:metabolism
chemical_list: D011506:Proteins; C570604:CFAP418 protein, human