Novel mutations of the carbohydrate sulfotransferase-6 (CHST6) gene causing macular corneal dystrophy in India

Purpose: Macular corneal dystrophy (MCD) is an autosomal recessive disorder characterized by progressive central haze, confluent punctate opacities and abnormal deposits in the cornea. It is caused by mutations in the carbohydrate sulfotransferase-6 (CHST6) gene, encoding corneal N-acetyl glucosamine-6-O-sulfotransferase (C-GlcNAc-6-ST). We screened the CHST6 gene for mutations in Indian families with MCD, in order to determine the range of pathogenic mutations. Methods: Genomic DNA was isolated from peripheral blood leukocytes of patients with MCD and normal controls. The coding regions of the CHST6 gene were amplified using three pairs of primers and amplified products were directly sequenced. Results: We identified 22 (5 nonsense, 5 frameshift, 2 insertion, and 10 missense) mutations in 36 patients from 31 families with MCD, supporting the conclusion that loss of function of this gene is responsible for this corneal disease. Seventeen of these mutations are novel. Conclusions: These data highlight the allelic heterogeneity of macular corneal dystrophy in Indian patients

Trans-ethnic study confirmed independent associations of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe ocular surface complications

Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes. Cold medicines including non-steroidal anti-inflammatory drugs and multi-ingredient cold medications are reported to be important inciting drugs. Recently, we reported that cold medicine related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement including severe ocular surface complications (SOC) is associated with HLA-A*02:06 and HLA-B*44:03 in the Japanese. in this study, to determine whether HLA-B*44:03 is a common risk factor for CM-SJS/TEN with SOC in different ethnic groups we used samples from Indian, Brazilian, and Korean patients with CM-SJS/TEN with SOC, and investigated the association between CM-SJS/TEN with SOC and HLA-B*44:03 and/or HLA-A*02:06. We found that HLA-B*44:03 was significantly associated with CM-SJS/TEN with SOC in the Indian and Brazilian but not the Korean population, and that HLA-A*02:06 might be weakly associated in the Korean-but not the Indian and Brazilian population.Ministry of Education, Culture, Sports, Science and Technology of the Japanese governmentJapanese Ministry of Health, Labour and WelfareKyoto Foundation for the Promotion of Medical ScienceIntramural Research Fund of Kyoto Prefectural University of MedicinePromotion Project of Knowledge-Based Industrial Clustering of Okinawa PrefectureKyoto Prefectural Univ Med, Dept Ophthalmol, Kyoto, JapanDoshisha Univ, Fac Life & Med Sci, Res Ctr Inflammat & Regenerat, Kyoto 602, JapanLV Prasad Eye Inst, Prof Brien Holden Eye Res Ctr, Hyderabad, Andhra Pradesh, IndiaUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilSeoul Natl Univ, Coll Med, Dept Ophthalmol, Seoul, South KoreaChonnam Natl Univ, Dept Ophthalmol, Kwangju, South KoreaYonsei Univ, Coll Med, Severance Hosp, Inst Vis Res,Dept Ophthalmol, Seoul, South KoreaCatholic Univ Korea, Seoul St Marys Hosp, Coll Med, Dept Ophthalmol & Visual Sci, Seoul, South KoreaLV Prasad Eye Inst, Cornea & Anterior Segment Serv, Hyderabad, Andhra Pradesh, IndiaUniv Tokyo, Grad Sch Med, Dept Human Genet, Tokyo, JapanUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilWeb of Scienc

NMNAT1 Mutations Cause Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss. Two-thirds of LCA cases are caused by mutations in 17 known disease genes (RetNet Retinal Information Network). Using exome sequencing, we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 as likely disease-causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in their kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide $(NAD^+)$ biosynthesis. Functional studies showed the p.Val9Met mutation decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated LCA families identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease and indicate that NMNAT1 mutations cause LCA

Kannabiran C: Genetic analysis of Indian families with autosomal recessive retinitis pigmentosa by homozygosity screening. Invest Ophthalmol Vis Sci 2009

PURPOSE. To identify the disease-causing genes in families with autosomal recessive RP (ARRP). METHODS. Families were screened for homozygosity at candidate gene loci followed by screening of the selected gene for pathogenic mutations if homozygosity was present at a given locus. A total of 34 families were included, of which 24 were consanguineous. Twenty-three genes were selected for screening. The presence of homozygosity was assessed by genotyping flanking microsatellite markers at each locus in affected individuals. Mutations were detected by sequencing of coding regions of genes. Sequence changes were tested for presence in 100 or more unrelated normal control subjects and for cosegregation in family members. RESULTS. Homozygosity was detected at one or more loci in affected individuals of 10 of 34 families. Homozygous disease cosegregating sequence changes (two frame-shift, two missense, and one nonsense; four novel) were found in the TULP1, RLBP1, ABCA4, RPE65, and RP1 genes in 5 of 10 families. These changes were absent in 100 normal control subjects. In addition, several polymorphisms and novel variants were found. All the putative pathogenic changes were associated with severe forms of RP with onset in childhood. Associated macular degeneration was found in three families with mutations in TULP1, ABCA4, and RP1 genes. Retinitis pigmentosa (RP) is the most common clinical expression, but this condition represents a clinical manifestation of diverse genetic errors that are inherited as autosomal dominant, recessive, X-linked, digenic, or mitochondrial disorders. The manifestation and course of RP can show considerable variation between individuals, and onset of the disease can vary from childhood to adolescence or early adulthood. Initial symptoms include night blindness in the early stages coupled with decreased visual acuity and progressive loss of visual fields. Clinically, changes in the retina include pallor of the optic disc, attenuated vasculature, pigmentary deposits appearing as bony spicules, atrophy of retinal tissue and diminished electroretinographic responses. The prevalence of RP ranges from 1 in 5000 to 1 in 1000 in different parts of the world. 1-3 ARRP appears to be relatively more common than dominant or X-inked forms in patient populations. This study was designed to identify genes underlying ARRP in affected families. We screened 34 ARRP families for homozygosity at 23 loci for possible involvement in disease. The 23 loci belong to a subset of loci commonly involved in RP and related disorders or were candidates based on expression and function. Screening was done in two stages. First, we performed genotyping of microsatellite markers flanking each of the 23 genes to test for homozygosity at any of these loci among affected individuals. In the second stage, we sequenced coding regions of genes present at homozygous regions for pathogenic mutations. METHODS The study protocol was approved by the Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. Probands with a family history suggestive of recessive RP were included in the study and available family members were enrolled. All subjects, both affected and unaffected, were clinically evaluated and informed consent was obtained. A total of 34 families with 2 or more affected individuals were recruited; 24 families were consanguineous and 10 were nonconsanguineous. Essential diagnostic criteria for inclusion included bilateral, diffuse, and widespread retinal pigment epithelial degeneration, arterial narrowing, commensurate visual field loss, and reduced amplitudes on electroretinogram (ERG) reduced to less than 25% of the maximum retinal response in normal individuals (normal amplitude of b-wave Ͼ350 V and a-wave Ͼ110 V) with evidence of rod and cone involvement. Other clinical signs that were supportive but not essential for diagnosis of RP included pigment migration including bonecorpuscular pigmentation, vitreous opacities and vitreous pigments, From th