ObjectiveThis current cross-sectional study aimed to investigate the demographic characteristics and molecular epidemiology of patients with Usher syndrome in the Turkish population.MethodsPatients who were followed up with a preliminary diagnosis of Usher syndrome from various regions of the country were included in the study. After a review of patients' medical histories, all underwent ophthalmological and otorhinolaryngological examinations. Mutations reported in previous studies in MYO7A, PCDH15, USH1C, CDH23, and USH2A were investigated using Sanger sequencing.ResultsFourteen (29.2%) patients had Usher syndrome type 1 and 16 (33.3%) had type 2. Eighteen (37.5%) patients could not be typed. We detected mutations in MYO7A (c.1343 + 1 G > A) in seven patients (six heterozygous and one homozygous) from seven families clinically compatible with Usher syndrome type 2 (rather than Usher syndrome type 1, as was expected based on previous studies).ConclusionsOur preliminary findings suggest that the proportions of patients with Usher syndrome type 1 and Usher syndrome type 2 in the Turkish population were almost equal, and none of our patients was clinically compatible with Usher syndrome type 3. Although previous studies reported that mutations in MYO7A rarely caused Usher syndrome type 2, in the Turkish population, MYO7A alleles may be hypomorphic and manifest as a milder phenotype in Usher syndrome compared with other populations.

Usher syndrome type 3 (USH3) is an autosomal recessive inherited disorder caused by pathogenic variants in the CLRN1 gene. To evaluate the genotype-phenotype correlation of Usher syndrome type 3 (USH3) in a deaf-blind Chinese family of 3 generations with 2 patients. We collected blood samples and clinical data from all of the pedigree family members. Genomic DNA was isolated from peripheral leukocytes using standard method. Targeted next generation sequencing and Sanger sequencing were performed to find the pathogenic variants in this family. Digital PCR and plasmid overexpression assay were used to verify the pathogenicity of variant sites in different transcripts. All patients developed bilateral sensorineural hearing loss (SHL), progressive vision loss and nyctalopia. NGS of genes for Usher syndrome, deafness and retinal dystrophy identified a locus mutation in CLRN1 that caused completely different amino acid changes in different transcripts[CLRN1:c.474T > A(P.Cys158Ter) at NM_001256819.2 or c.302T > A(p.Val101Asp) at NM_174878.3], and plasmid overexpression experiments confirmed that the c.474T > A(P.Cys158Ter, NM_001256819.2) was a pathogenic variant which has never been associated with Usher syndrome in China, and the transcript of this mutation was not the version commonly found worldwide. The CLRN1c.474T > A(NM_001256819.2) mutation is the causative variant in the Chinese family with USH3. The pathogenicity of different transcripts should be particularly considered in pathogenicity analysis.

A 30-year-old female presented with gradually progressive diminution of vision for 1 month, with night blindness for the past 5 years and difficulty in hearing for the past 10 years. Her developmental history and family history were unremarkable. Ocular examination revealed visual acuity of 6/36 in both eyes. Fundus showed features of retinitis pigmentosa with bilateral macular edema. Audiometry revealed bilateral sensorineural hearing loss; although, her vestibular functions were preserved. Clinical diagnosis of Usher syndrome type 3 was made based on normal hearing at birth, delayed presentation of progressive visual and auditory impairment with normal vestibular function, and developmental milestones. Her macular edema resolved after 3 months of treatment with topical dorzolamide therapy. The unique feature of this case is the presence of bilateral macular edema in type 3 Usher syndrome, which is rarely reported in literature.

Usher syndrome type 3 (USH3) is an autosomal recessively inherited disorder caused by mutations in the gene clarin-1 (CLRN1), leading to combined progressive hearing loss and retinal degeneration. The cellular distribution of CLRN1 in the retina remains uncertain, either because its expression levels are low or because its epitopes are masked. Indeed, in the adult mouse retina, Clrn1 mRNA is developmentally downregulated, detectable only by RT-PCR. In this study we used the highly sensitive RNAscope in situ hybridization assay and single-cell RNA-sequencing techniques to investigate the distribution of Clrn1 and CLRN1 in mouse and human retina, respectively. We found that Clrn1 transcripts in mouse tissue are localized to the inner retina during postnatal development and in adult stages. The pattern of Clrn1 mRNA cellular expression is similar in both mouse and human adult retina, with CLRN1 transcripts being localized in Müller glia, and not photoreceptors. We generated a novel knock-in mouse with a hemagglutinin (HA) epitope-tagged CLRN1 and showed that CLRN1 is expressed continuously at the protein level in the retina. Following enzymatic deglycosylation and immunoblotting analysis, we detected a single CLRN1-specific protein band in homogenates of mouse and human retina, consistent in size with the main CLRN1 isoform. Taken together, our results implicate Müller glia in USH3 pathology, placing this cell type to the center of future mechanistic and therapeutic studies to prevent vision loss in this disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Usher syndrome (USH) is a clinically common autosomal recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction. In this study, we identified a Hunan family of Chinese descent with two affected members clinically diagnosed with Usher syndrome type 3 (USH3) displaying hearing, visual acuity, and olfactory decline. Whole-exome sequencing (WES) identified a nonsense variant in ABHD12 gene that was confirmed to be segregated in this family by Sanger sequencing and exhibited a recessive inheritance pattern. In this family, two patients carried homozygous variant in the ABHD12 (NM_015600: c.249C>G). Mutation of ABHD12, an enzyme that hydrolyzes an endocannabinoid lipid transmitter, caused incomplete PHARC syndrome, as demonstrated in previous reports. Therefore, we also conducted a summary based on variants in ABHD12 in PHARC patients, and in PHARC patients showing that there was no obvious correlation between the genotype and phenotype. We believe that this should be considered during the differential diagnosis of USH. Our findings predicted the potential function of this gene in the development of hearing and vision loss, particularly with regard to impaired signal transmission, and identified a novel nonsense variant to expand the variant spectrum in ABHD12.