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.

The role of primary cilia in the development and disease of the retina

“…Refer to Table S1 for further details. Novel uncharacterised proteins are still being discovered to play a role in such processes, such as C8orf37, a ciliary protein which is mutated in CORD and RP 232 and C2orf71, a ciliary protein mutated in RP in humans and progressive retinal atrophy in several breeds of dog. 233,234 While our understanding of primary cilia and specialized sensory cilia such as the photoreceptor has advanced greatly in the past two decades, there still remains much to discover.…”

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

“…1-3 CRD can manifest under a variety of inheritance models, though the autosomal recessive mode of inheritance is the most prevalent. To date, eight genes responsible for autosomal recessive CRD have been identified: ABCA4 (OMIM#601691), 4 ADAM9 (OMIM#602713), 5 C8orf37 (OMIM#614477), 6 CERKL (OMIM#608381), 7 EYS (OMIM#612424), 8 RPGRIP1 (OMIM#605446), 9 RAB28 (OMIM#612994) 10 and TULP1 (OMIM#602280). 11 However, the known variants do not account for all cases of CRD.…”

Mutations in MFSD8, Encoding a Lysosomal Membrane Protein, Are Associated with Nonsyndromic Autosomal Recessive Macular Dystrophy

“…Three of these genes initially have been associated with ACHM, a form of cone dysfunction that can develop into COD. Eighteen genes have been associated with ar CRD (ABCA4, 17 ADAM9, 18 C8orf37, 19 CDHR1, 20,21 CERKL, 22 CNGB3, 23 CRB1, 24 CRX, 24 EYS, 25 FSCN2, 26 GUCY2D, 27 KCNV2, 14 PDE6C, 23 POC1B, 28,29 PROM1, 30 RAB28, 31 RPE65, 24 RPGRIP1, 23 and TULP1 16 ). In both disorders, mutations in these genes explain disease in an estimated 21% (COD) and 25% (CRD) of patients.…”