A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome

Khateb, Samer; Zelinger, Lina; Mizrahi-Meissonnier, Liliana; Ayuso, Carmen; Koenekoop, Robert K.; Laxer, Uri; Gross, Menachem; Banin, Eyal; Sharon, Dror

doi:10.1136/jmedgenet-2014-102287

Cited by 80 publications

(83 citation statements)

References 39 publications

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“…Next, we designed morpholino oligonucleotides (MO) for both genes: a splice blocker for rp1l1 , and a translational blocker for c2orf71l due to the lack of useable designs for a splice blocker. As a first test, we evaluated the impact of suppression of each of the two genes on early gastrulation; both genes have been shown to be relevant to ciliary function, 7–9 perturbation of which induces convergent extension (CE) defects in mid-somitic embryos. 10,11 Consistent with this expectation, suppression of each of rp1l1 and c2orf71l induced CE defects; embryos with an expansion of the “gap angle” (>45°) were considered affected and were plotted as such (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…28 Interestingly, a heterozygous C2orf71 null allele in combination with a homozygous nonsense mutation in CEP250 was associated with atypical Usher syndrome, characterized by early-onset sensorineural hearing loss and a relatively mild form of RP. 9 In a double homozygote of these variants the retina was more severely affected suggesting an additive effect in these ciliary proteins.…”

Section: Discussionmentioning

confidence: 99%

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Putative digenic inheritance of heterozygousRP1L1andC2orf71null mutations in syndromic retinal dystrophy

Liu

Bosch

Siemiątkowska

et al. 2016

Ophthalmic Genetics

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Background Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. Materials and methods In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity. Results Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Q2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. Conclusions We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Putative digenic inheritance of heterozygousRP1L1andC2orf71null mutations in syndromic retinal dystrophy

Liu

Bosch

Siemiątkowska

et al. 2016

Ophthalmic Genetics

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“…Additionally, some evidence have shown the potential involvement of CEP78 in retinal and hearing abnormalities: CEP78 was identified to interact with cilia protein CEP250,30 and the latter is a known Usher syndrome protein 31. In another study, researchers tried identifying crucial genes which show significantly altered expression in cochlea after noise-induced hearing loss and CEP78 was among the 15 genes with more than fivefold upregulation.…”

Section: Discussionmentioning

confidence: 99%

CEP78is mutated in a distinct type of Usher syndrome

Xue

et al. 2016

J Med Genet

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Background Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20–30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome. Methods Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants. Results Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone–rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift. Conclusions Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells.

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“…To date, sixteen loci have been associated with USH: nine are involved in USH1, three in USH2, two in USH3 and two not specified (Table 1) [9, 23–27]. From these loci, thirteen genes have been identified.…”

Section: Genes and Loci Identified In Ush Patientsmentioning

confidence: 99%

“…CLRN1 (Clarin-1) and HARS (histidyl-tRNA synthetase) are the USH3 genes [25, 40–42]. Furthermore, PDZD7 (PDZ domain containing 7) was recently discovered as an USH modifier and digenic USH contributor gene [26], and CEP250 as an atypical USH gene [27]. Among these genes, HARS is debatable as an USH3 gene, because patients carrying mutations in this gene develop episodic psychosis as well as progressive hearing loss and RP [25], which could be clinical symptoms of other rare syndromes.…”

Section: Genes and Loci Identified In Ush Patientsmentioning

confidence: 99%

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

Mathur

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

285

301

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Usher syndrome (USH), clinically and genetically heterogeneous, is the leading genetic cause of combined hearing and vision loss. USH is classified into three types, based on the hearing and vestibular symptoms observed in patients. Sixteen loci have been reported to be involved in the occurrence of USH and atypical USH. Among them, twelve have been identified as causative genes and one as a modifier gene. Studies on the proteins encoded by these USH genes suggest that USH proteins interact among one another and function in multiprotein complexes in vivo. Although their exact functions remain enigmatic in the retina, USH proteins are required for the development, maintenance and function of hair bundles, which are the primary mechanosensitive structure of inner ear hair cells. Despite the unavailability of a cure, progress has been made to develop effective treatments for this disease. In this review, we focus on the most recent discoveries in the field with an emphasis on USH genes, protein complexes and functions in various tissues as well as progress toward therapeutic development for USH.

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A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome

Cited by 80 publications

References 39 publications

Putative digenic inheritance of heterozygousRP1L1andC2orf71null mutations in syndromic retinal dystrophy

Putative digenic inheritance of heterozygousRP1L1andC2orf71null mutations in syndromic retinal dystrophy

CEP78is mutated in a distinct type of Usher syndrome

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

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