PURPOSE: Pre-Descemet corneal dystrophy (PDCD) with X-linked ichthyosis (XLI) is associated with mutations in or deletions of the steroid sulfatase gene (STS). As only three cases of genetically confirmed PDCD associated with XLI have been reported, we sought to expand our understanding of the genetic basis of PDCD by screening STS in two previously unreported families. MATERIALS AND METHODS: The affected individuals underwent cutaneous and slit-lamp examinations. Saliva samples collected from each affected individual served as a source of DNA for the amplification of the 10 coding exons of STS and flanking DNA markers. RESULTS: The slit-lamp examination of three affected men (two of whom were brothers) from two families revealed bilateral punctate posterior corneal stromal opacities anterior to the Descemet membrane. Cutaneous examination demonstrated dry, coarse, scaly ichthyotic changes characteristic of XLI in all individuals. Genetic examination of the STS locus on the X chromosome in Case 1 revealed a deletion that spanned across DNA markers DXS1130-DXS237, which includes all the coding exons (exons 1-10) of STS. Genetic screening of Cases 2 and 3 revealed a partial deletion of the STS locus involving exons 1-7 and flanking DNA marker DXS1130 on the X chromosome. CONCLUSIONS: PDCD with XLI may be associated with either partial or complete deletion of STS. Despite the identification of point mutations, partial deletion, and complete deletion of STS in different affected families reported to date, there was no apparent difference in the affected phenotype between the families, suggesting that the identified variants likely all resulted in loss of function of steroid sulfatase.

BACKGROUND: Mutations in the USH2A gene are the leading cause of both non-syndromic autosomal recessive retinitis pigmentosa (RP) and Usher syndrome, a syndromic form of RP characterized by retinal dystrophy and sensorineural hearing loss. To contribute to the expansion of the USH2A-related molecular spectrum, the results of genetic screening in a large cohort of Mexican patients are presented. METHODS: The study population comprised 61 patients with a clinical diagnosis of either non-syndromic RP (n = 30) or Usher syndrome type 2 (USH2; n = 31) who were demonstrated to carry biallelic pathogenic variants in USH2A in a three-year period. Genetic screening was performed either by gene panel sequencing or by exome sequencing. A total of 72 available first- or second-degree relatives were also genotyped for familial segregation of the identified variants. RESULTS: The USH2A mutational spectrum in RP patients included 39 distinct pathogenic variants, most of them of the missense type. The most common RP-causing variants were p.Cys759Phe (c.2276G>T), p.Glu767Serfs*21 (c.2299delG), and p.Cys319Tyr (c.956G>A), which together accounted for 25% of all RP variants. Novel USH2A mutations included three nonsense, two missense, two frameshift, and one intragenic deletion. The USH2A mutational spectrum in USH2 patients included 26 distinct pathogenic variants, most of them of the nonsense and frameshift types. The most common Usher syndrome-causing variants were p.Glu767Serfs*21 (c.2299delG), p.Arg334Trp (c.1000C>T), and c.12067-2A>G), which together accounted for 42% of all USH2-related variants. Novel Usher syndrome USH2A mutations included six nonsense, four frameshift, and two missense mutations. The c.2299delG mutation was associated with a common haplotype for SNPs located in exons 2-21 of USH2A, indicating a founder mutation effect. CONCLUSIONS: Our work expands the USH2A mutational profile by identifying 20 novel pathogenic variants causing syndromic and non-syndromic retinal dystrophy. The prevalent c.2299delG allele is shown to arise from a founder effect. Our results emphasize the usefulness of molecular screening in underrepresented populations for a better characterization of the molecular spectrum of common monogenic diseases.

PURPOSE: This study sought to describe the phenotype frequency and genetic basis of inherited retinal diseases (IRDs) among a nationwide cohort of Israeli Jewish patients of Ethiopian ancestry. METHODS: Patients' data-including demographic, clinical, and genetic information-were obtained through members of the Israeli Inherited Retinal Disease Consortium (IIRDC). Genetic analysis was performed by either Sanger sequencing for founder mutations or next-generation sequencing (targeted next-generation sequencing or whole-exome sequencing). RESULTS: Forty-two patients (58% female) from 36 families were included, and their ages ranged from one year to 82 years. Their most common phenotypes were Stargardt disease (36%) and nonsyndromic retinitis pigmentosa (33%), while their most common mode of inheritance was autosomal recessive inheritance. Genetic diagnoses were ascertained for 72% of genetically analyzed patients. The most frequent gene involved was ABCA4. Overall, 16 distinct IRD mutations were identified, nine of which are novel. One of them, ABCA4-c.6077delT, is likely a founder mutation among the studied population. CONCLUSIONS: This study is the first to describe IRDs' phenotypic and molecular characteristics in the Ethiopian Jewish community. Most of the identified variants are rare. Our findings can help caregivers with clinical and molecular diagnosis and, we hope, enable adequate therapy in the near future.

PURPOSE: Basigin gene products are positioned on adjacent cell types in the neural retina and are thought to compose a lactate metabolon important for photoreceptor cell function. The Ig0 domain of basigin isoform 1 (basigin-1) is highly conserved throughout evolution, which suggests a conserved function. It has been suggested that the Ig0 domain has proinflammatory properties, and it is hypothesized to interact with basigin isoform 2 (basigin-2) for cell adhesion and lactate metabolon formation. Therefore, the purpose of the present study was to determine whether the Ig0 domain of basigin-1 binds to basigin-2 and whether the region of the domain used for binding is also used to stimulate interleukin-6 (IL-6) expression. METHODS: Binding was assessed using recombinant proteins corresponding to the Ig0 domain of basigin-1 and endogenously expressed basigin-2 from mouse neural retina and brain protein lysates. The proinflammatory properties of the Ig0 domain were analyzed with exposure of the recombinant proteins to the mouse monocyte RAW 264.7 cell line and subsequent measurement of the IL-6 concentration in the culture medium via enzyme-linked immunosorbent assay (ELISA). RESULTS: The data indicate that the Ig0 domain interacts with basigin-2 through a region within the amino half of the domain and that the Ig0 domain does not stimulate the expression of IL-6 in mouse cells in vitro. CONCLUSIONS: The Ig0 domain of basigin-1 binds to basigin-2 in vitro. In addition, contrary to previous reports, there was no evidence that the Ig0 domain potentiates IL-6 expression in a mouse monocyte cell line in vitro. However, it is possible that the Ig0 domain stimulates the expression of proinflammatory cytokines other than IL-6, or that the potential involvement of the Ig0 domain of basigin-1 in the acute inflammatory response is dependent on species.