Linkage of a gene for macular corneal dystrophy to chromosome 16.
Ontology highlight
ABSTRACT:
SUBMITTER: Vance JM
PROVIDER: S-EPMC1914688 | biostudies-other | 1996 Apr
REPOSITORIES: biostudies-other
Publications
Linkage of a gene for macular corneal dystrophy to chromosome 16.
Vance J M JM Jonasson F F Lennon F F Sarrica J J Damji K F KF Stauffer J J Pericak-Vance M A MA Klintworth G K GK
American journal of human genetics 19960401 4
Autosomal recessive macular corneal dystrophy (MCD) is a heterogeneous disorder leading to visual impairment. Sixteen American and Icelandic families (11 type I and 5 type II) were analyzed for linkage, by use of 208 polymorphic microsatellite markers. A significant maximum LOD score Zmax of 7.82 at a maximum recombination fraction (thetamax) of .06 was found with the 16q22 locus D16S518 for MCD type I. In addition, a peak LOD score of 2.50 at a recombination fraction of .00 was obtained for the ...[more]
Similar Datasets
Project description:PurposeTo identify the molecular genetic cause of macular corneal dystrophy (MCD) in four probands, and characterize phenotypic similarities between MCD and keratoconus.MethodsWe performed ophthalmological examination, Scheimpflug imaging (Pentacam, Oculus Inc.), histopathological examination of excised corneal buttons, and direct sequencing of the CHST6 coding region.ResultsPentacam measurements were taken in six eyes of three probands. All showed diffuse corneal thinning with paracentral steepening of the anterior corneal surface that was graded as keratoconus by the integrated software, but without associated ectasia of the posterior corneal surface or regional thinning. Homozygous or compound heterozygous CHST6 mutations were identified in all cases, including two novel mutations, c.13C>T; p.(Arg5Cys) and c.289C>T; p.(Arg97Cys).DiscussionLocalized elevation of the anterior corneal curvature can occur in MCD in the absence of other features of keratoconus. The identification of a further two Czech probands with the compound allele c.[484C>G; 599T>G] supports the enrichment of this allele in the study population.
| S-EPMC4194335 | biostudies-literature
Project description:PurposeMacular Corneal Dystrophy (MCD, MIM #217800) is a category 1 corneal stromal dystrophy as per the current IC3D classification. While characterized by macular stromal deposits, we report a case of MCD type II with isolated bilateral peripheral Decemet membrane opacities, describing the clinical features and results of screening the CHST6 gene and serum sulfated keratan sulfate levels.ObservationsA 68-year-old man with an unremarkable past medical and family history presented with bilateral progressive decrease in vision. Ocular exam revealed bilateral clear corneas with the exception of peripheral, round, gray-white discrete deposits at the level of Descemet membrane and decreased central corneal thickness in both eyes. The morphology of the corneal deposits, decreased corneal thickness and the absence of a family history were consistent with MCD, prompting screening of the CHST6 gene. Sanger sequencing followed by allele specific cloning revealed compound heterozygous CHST6 mutations in trans configuration: c.-26C > A, which created a new upstream open reading frame (uORF'), predicted to attenuate translation efficiency of the downstream main ORF; and c.803A > G (p.(Tyr268Cys)), previously associated with MCD. Serum keratan sulfate was reduced but detectable, consistent with the diagnosis of macular corneal dystrophy type II.ConclusionsAlthough macular corneal dystrophy is classified as a corneal stromal dystrophy with endothelial involvement, we report a case of MCD with dystrophic deposits confined to the peripheral Descemet membrane, indicating that MCD may be associated with isolated endothelial involvement.
| S-EPMC6881691 | biostudies-literature
Project description:PurposeTo perform a genome-wide linkage screen with a single-nucleotide polymorphism (SNP) linkage panel to identify regions of genetic linkage in Fuchs endothelial corneal dystrophy (FECD) and to analyze affected individuals for mutations in the COL8A2 gene.MethodsNinety-two individuals from 22 families with FECD were identified from our multiplex FECD family cohort. A genome-wide linkage scan was performed using an SNP linkage panel. Parametric two-point linkage analyses were calculated and nonparametric multipoint linkage analyses were performed on chromosomes with two-point LOD scores (HLOD) > 1.0. All affected individuals were analyzed for the two previously reported FECD mutations in the COL8A2 gene (L450W and Q455K).ResultsThe genome-wide analysis identified five regions with linkage signals from all analyses on chromosomes 1, 7, 15, 17, and X. The highest two-point HLODs were found on the long arm of chromosome 15 with an HLOD of 3.26 for the recessive model and 2.48 for the dominant model. Multipoint linkage analysis also identified a linkage peak on the long arm of chromosome 15 with a LOD > 1. The region of linkage on chromosome 1p, driven by two multigenerational FECD families with a two-point LOD > 2, was adjacent to the previously identified COL8A2 gene; however, the two reported mutations in COL8A2 were not identified in any of the 56 affected individuals in the 92 samples tested.ConclusionsGenome-wide linkage analysis was used to identify potential linkage regions on chromosomes 1, 7, 15, 17, and X for FECD. The previously reported mutations in the COL8A2 gene were not found in the 92 samples tested.
| S-EPMC2712757 | biostudies-literature
Project description:BackgroundMacular corneal dystrophy (MCD) is a rare autosomal recessive disorder that is characterized by progressive corneal opacity that starts in early childhood and ultimately progresses to blindness in early adulthood. The aim of this study was to identify the cause of MCD in a black South African family with two affected sisters.MethodsA multigenerational South African Sotho-speaking family with type I MCD was studied using whole exome sequencing. Variant filtering to identify the MCD-causal mutation included the disease inheritance pattern, variant minor allele frequency and potential functional impact.ResultsOphthalmologic evaluation of the cases revealed a typical MCD phenotype and none of the other family members were affected. An average of 127 713 variants per individual was identified following exome sequencing and approximately 1.2 % were not present in any of the investigated public databases. Variant filtering identified a homozygous E71Q mutation in CHST6, a known MCD-causing gene encoding corneal N-acetyl glucosamine-6-O-sulfotransferase. This E71Q mutation results in a non-conservative amino acid change in a highly conserved functional domain of the human CHST6 that is essential for enzyme activity.ConclusionWe identified a novel E71Q mutation in CHST6 as the MCD-causal mutation in a black South African family with type I MCD. This is the first description of MCD in a black Sub-Saharan African family and therefore contributes valuable insights into the genetic aetiology of this disease, while improving genetic counselling for this and potentially other MCD families.
| S-EPMC4955246 | biostudies-literature
Project description:BackgroundCorneal dystrophies are a group of rare, inherited disorders that are usually bilateral, symmetric, slowly progressive, and not related to environmental or systemic factors. The majority of publications present the advanced form of the disease with a typical clinical demonstration. The initial signs and symptoms of different epithelial and stromal corneal dystrophies are not specific; therefore, it is very important to establish the early characteristic corneal features of these disorders that could guide the diagnostic process.Case presentationThe main purpose of this study was to report the differential diagnosis of a pediatric patient with bilateral anterior corneal involvement suspected of corneal dystrophy. An 8-year-old male patient presented with asymptomatic, persistent, superficial, bilateral, diffuse, anterior corneal opacities. Slit lamp examination results were not specific. Despite the lack of visible stromal involvement on the slit lamp examination, corneal analysis based on confocal microscopy and optical coherence tomography revealed characteristic features of macular corneal dystrophy (MCD). The diagnosis of MCD was confirmed by CHST6 gene sequencing. The early corneal characteristic features of MCD, established based on the findings of this case report, include corneal astigmatism (not specific), diffuse corneal thinning without a pattern of corneal ectasia (specific), and characteristic features on confocal microscopy (specific), including multiple, dark, oriented striae at different corneal depths.ConclusionsThe clinical examination should be complemented with corneal imaging techniques, such as confocal microscopy and optical coherence tomography. In patients suspected of corneal dystrophy, genetic testing plays an important role in establishing the final diagnosis.
| S-EPMC8299585 | biostudies-literature
Project description:Macular corneal dystrophy (MCD) is an autosomal recessive disorder mainly caused by gene mutations of carbohydrate sulfotransferase (CHST6) leading to bilateral visual impairment. Because the mechanism underlying this degeneration remains poorly understood, we investigated molecular alterations and pathways that may be involved in MCD in this issue. Different mutation sites were screened by direct sequencing of the coding region of CHST6. In addition, we described morphological changes in MCD keratocytes by light microscopy and electron microscopy and determined the relationship between the development of this disease and the occurrence of apoptosis through flow cytometry, cell counting kit-8, colony formation assay and other experiments. Western blotting and quantitative real-time polymerase chain reaction were used to determine if endoplasmic reticulum (ER) stress was activated. We found 10 kinds of mutations among these families with 3 novel mutations included. The percentage of apoptotic keratocytes increased in MCD patients; furthermore, the expression of apoptosis related protein B-cell lymphoma-2 (Bcl-2) was down-regulated while Bcl-2 associated X protein was upregulated. Finally, ER stress was activated with the upregulation of glucose-regulated protein 78 and CCAAT-enhancer-binding protein homologous protein. Our clinical and in vitro results suggest that the CHST6 mutation associated with MCD is associated with apoptosis, and ER stress is probably involved in this apoptosis pathway.
| S-EPMC5707101 | biostudies-literature
Project description:PurposeTo characterize mutations within the carbohydrate sulfotransferase 6 (CHST6) gene in Iranian subjects from 12 families with macular corneal dystrophy (MCD).MethodsGenomic DNA was extracted from peripheral blood of 20 affected patients and 60 healthy volunteers followed by polymerase chain reaction (PCR) and direct sequencing of the CHST6 coding region. The observed nucleotide sequences were then compared with those found by investigators in other populations with MCD and in the controls.ResultsAnalysis of CHST6 revealed 11 different mutations. These mutations were comprised of six novel missense mutations (p.F55L, p.P132L, p.S136G, p.C149Y, p.D203Y, and p.H249R), one novel nonsense mutation (p.S48X), one novel frame shift (after P297), and three previously reported missense mutations (p.P31L, p.C165Y, and p.R127C). The majority of the detected MCD mutations are located in the binding sites or the binding pocket, except the p.P31L and p.H249R mutations.ConclusionsNucleotide changes within the coding region of CHST6 are predicted to significantly alter the encoded sulfotransferase within the evolutionary conserved sequences. Our findings show that CHST6 mutations are responsible for the pathogenesis of MCD in Iranian patients. Moreover, the observation that some cases of MCD cannot be explained by mutations in the coding region of CHST6 suggests that MCD may result from possible upstream rearrangements in the CHST6 genomic region.
| S-EPMC2642847 | biostudies-literature
Project description:PurposeTo identify the genetic basis of posterior amorphous corneal dystrophy (PACD) segregating in a large pedigree.MethodsThe authors performed clinical evaluation of a previously unreported pedigree with PACD, light and electron microscopic examination of an excised corneal button, genomewide linkage analysis, fine mapping linkage and haplotype analysis, and screening of four candidate genes (KERA, LUM, DCN, and EPYC).ResultsTwenty-one participants were determined to be affected based on the presence of characteristic clinical features of PACD; 15 affected and 39 unaffected individuals from a single pedigree enrolled in the study and provided DNA for analysis. Histopathologic examination of an excised corneal specimen from an affected individual demonstrated disorganized stromal lamellae and stromal staining with colloidal iron. Genomewide analysis demonstrated significant evidence of linkage to chromosome region 12q21.33 and evidence suggestive of linkage to chromosome region 8q22.3. Fine mapping of the chromosome 12 locus confirmed significant linkage; the largest multipoint log odds ratio score was 5.6 at D12S351. The linkage support interval was approximately 3.5 Mb (3.5 cM) in length between flanking markers D12S1812 and D12S95, roughly the entire chromosome band 12q21.33. No coding region mutations were identified in four candidate genes-KERA, LUM, DCN, EPYC-located in the chromosome 12 linkage support interval.ConclusionsLinkage and haplotype analyses identified 12q21.33 as a locus for PACD. However, no mutations were identified in the candidate genes (KERA, LUM, DCN, EPYC) within this region.
| S-EPMC2910638 | biostudies-literature
Project description:To report a novel mutation within the CHST6 gene, as well as describe light and electron microscopic features of a case of macular corneal dystrophy. A 59-year old woman with macular corneal dystrophy in both eyes who had decreased visual acuity underwent penetrating keratoplasty. Further studies including light and electron microscopy, as well as DNA analysis were performed. Light microscopy of the cornea revealed glycosaminoglycan deposits in the keratocytes and endothelial cells, as well as extracellularly within the stroma. All samples stained positively with alcian blue, colloidal iron, and periodic acid-Schiff. Electron microscopy showed keratocytes distended by membrane-bound intracytoplasmic vacuoles containing electron-dense fibrillogranular material. These vacuoles were present in the endothelial cells and between stromal lamellae. Some of the vacuoles contained dense osmophilic whorls. A novel homozygous mutation (c.613 C>T [p.Arg205Trp]) was identified within the whole coding region of CHST6. A novel CHST6 mutation was detected in a Korean macular corneal dystrophy patient.
| S-EPMC3849310 | biostudies-literature
Project description:Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degeneration characterized by multiple glistening intraretinal dots scattered over the fundus, degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. Although BCD has been associated with abnormalities in fatty-acid metabolism and absence of fatty-acid binding by two cytosolic proteins, the genetic basis of BCD is unknown. We report linkage of the BCD locus to D4S426 (maximum LOD score [Z(max)] 4.81; recombination fraction [straight theta] 0), D4S2688 (Zmax=3.97; straight theta=0), and D4S2299 (Zmax=5.31; straight theta=0), on chromosome 4q35-4qtel. Multipoint analysis confirmed linkage to the region telomeric of D4S1652 with a Z(max) of 5.3 located 4 cM telomeric of marker D4S2930.
| S-EPMC1288572 | biostudies-literature