Novel Recessive Cone-Rod Dystrophy Caused byPOC1BMutation

Abstract

IMPORTANCE A new form of cone-rod dystrophy (CORD) is described and the gene responsible for the disease is identified. OBJECTIVE To clinically evaluate 4 patients and 5 control relatives, perform disease gene mapping, and identify the gene defect responsible for CORD. DESIGN, SETTING, AND PARTICIPANTS Prospective observational case series of 13 members of a consanguineous family and 113 unrelated control individuals. INTERVENTIONS Clinical investigations included eye examination with color fundus and autofluorescent imaging, spectral-domain optical coherence tomography, and electrophysiologic measurements. Linkage mapping was performed using single-nucleotide polymorphism genotype data. Candidate genes were analyzed for mutations via Sanger sequencing. MAIN OUTCOMES AND MEASURES Clinical diagnosis of CORD, disease gene mapping, and mutation identification. RESULTS The onset of CORD occurred in early childhood. The clinical phenotype was typical CORD with photophobia, decreased central vision, and dyschromatopsia. In all patients, a disrupted inner segment/outer segment line and the external limiting membrane were noted as a single blurry line at the central fovea, and the cone outer segment tip line was absent. In the midperipheral retina, the rod inner segment/outer segment line was disrupted and blurry, and the rod outer segment tip line was absent. Cone response was nonrecordable in all patients, whereas rod response was nonrecordable in the eldest patient and subnormal in the others. The Arden Index was abnormal in the youngest patient and flat in the others. The disease gene mapped to a less than 2-megabase recessive locus at 12q21.33 with a logarithm of odds score of 3.92. At the locus, we identified a homozygous missense POC1B p.R106P mutation that was predicted as damaging by online tools. CONCLUSIONS AND RELEVANCE POC1B is a novel gene for a new disease typical of CORD except that patients did not report night blindness. The clinical course was slowly progressive. Screening for POC1B mutation could benefit families afflicted with CORD.

Phenotypical Characteristics ofPOC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance

“…WD40 typically contains a GH dipeptide, 11 to 24 residues from its N terminus and a WD dipeptide at its C terminus of 40 residues long, hence the name WD40. Clinical and genetic findings of four affected subjects in a consanguineous Turkish family with CORD were also reported by Durlu et al 30 in 2014. The recurrent variant c.317G>C, p.Arg106Pro was identified in an Iraqi patient with a severe syndromic retinal ciliopathy in a consanguineous family.…”

“…31 Thus far, only 11 patients from 6 families with biallelic POC1B variants have been reported to have retinal abnormalities except in the Japanese patients (Table 6). [27][28][29][30][31]33 We have presented eight Japanese patients from seven families. According to previous reports, a wide variety of phenotypes were observed: one case of LCA, seven cases of CORD, and three cases of COD.…”

“…POC1B is expressed predominantly in the ciliary region of photoreceptor cells and synapses of the outer plexiform layer of the retina, 29 and homozygous or compound heterozygous mutations in the POC1B gene have been reported in cases with COD or cone-rod dystrophy (CORD), 27,29,30 Leber's congenital amaurosis (LCA) with syndromic ciliopathy, 31 and peripheral COD. 28 The funduscopic appearance in these cases varied from normal to peripheral abnormalities and small colobomas with small diameter vessels.…”

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.…”

Knockdown of poc1b causes abnormal photoreceptor sensory cilium and vision impairment in zebrafish

“…Poc1b has been shown to act with Poc1a, one of the two isoforms of Poc1 protein, at the centriole/basal body to ensure centriole integrity in human cells [26]. In the retina, FAM161A was found to be a binary interaction partner of POC1B, and their interaction was disrupted when mutant POC1B was present [16]. As a RP disease gene, FAM161A has been found to interact with several other ciliopathic genes/proteins as well, including lebercilin, CEP290, OFD1 and SDCCAG8 [27,28].…”