[A genome-wide screening for pathological myopia suggests a novel locus on chromosome 15q12 - 13].

OBJECTIVE: Pathological myopia has a genetic background. Previous studies have mapped six loci at 18p11.31, 12q21-23, 7q36, 17q21-22, 4q22-q27 and 2q37.1 in autosomal dominant (AD) pathological myopia. The aim of the present study was to map the mutate gene associated with this disorder in Chinese population. METHODS: A family with AD pathological myopia including 12 individuals, of which 7 members were affected, consented to participate our study. Three hundred and thirty pairs of highly heterozygous microsatellite marker primers were selected for a genome-wide screening. Two-point linkage was calculated by LINKAGE package in an autosomal dominant mode with full penetrance at gene frequency of 0.0133. Multipoint LOD scores were calcu1ated by use of GENEHUNTER program. Genetic distance between marker loci examined was determined on the basis of Genethon linkage map. Haplotype analysis was performed by software of Cyrillic 2.0 based on the lowest recombination principle. RESULTS: Evidence of significant linkage was found on chromosome 15q in the family by two-point linkage analysis. The maximum LOD score was 1.76 with the markers D15S1010, D15S1007 and D15S1042 at a recombination fraction of 0.00. Multipoint linkage analysis also supported existence of linkage on this region with NPL score 5.16. Haplotype analysis refined this myopia locus to a 12 cM interval between D15S1019 and D15S146 on 15q12 - 13. No evidence of linkage was found at any known myopia loci, including AD pathological myopia loci on 18p11.31, 12q21 - 23, 7q36, 17q21 - 22, 4q22 - q27 and 2q37.1, and syndromic myopia loci on 15q15-21, 12q13.11-13.2, 6p21.3, 1q21-31, 1p21 and 21q22.3. CONCLUSIONS: Our study indicates a novel myopia locus on 15q12 - 13. There are 94 known genes locate on this region, screening for sequence of candidate genes within this region will be helpful to find the mutant gene. This study also provides additional support for genetic heterogeneity of this disorder.

A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia.

BACKGROUND: hidrotic ectodermal dysplasia (HED) or Clouston syndrome is a rare autosomal dominant disorder affecting the skin and its derivatives. It is characterized by the triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis. To date, all mutations have been involving in three codons: G11R, A88V and V37E in the connexin 30 (Cx30) gene have been shown to cause this disorder. OBJECTIVE: in order to analyze the mutations of the Cx30 gene in Chinese Han patients with HED. METHODS: we collected a large Chinese HED family consisting of a total of 81 individuals including 28 HED patients (14 males and 14 females). The whole coding region of Cx30 was amplified by polymerase chain reaction and products analyzed by direct sequencing, then further confirmed at the mRNA level by RT-PCR. RESULTS: we detected a transition, 31(G-->A), leading to a missense mutation (G11R) in genomic DNAs of 18 patients, and the point mutation was not found in 16 normal individuals in this HED family and in 188 unrelated, population-match control individuals. The transcription of mutated allele was confirmed by RT-PCR of Cx30 mRNA. CONCLUSION: our data suggests that a G11R missense mutation in the Cx30 gene can cause HED in Chinese Han population and emphasizes the importance of screening for this as well as other Cx30 gene mutations in the HED.

KCNQ1 gain-of-function mutation in familial atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.

Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans.

Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9-62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (alpha) and a maximum multipoint heterogeneity lod score of 4.25 (alpha=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (alpha=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (alpha=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes.

Study on the Mechanism of Fibronectin Adhesion to NIH3T3 cell Stimulated by Retinoic Acid.

Retinoic acid (RA) is an inducer of cell differentiation. Recently, it was discovered that RA widely works on cells, causing a series of physiological alterations, and may make the tumor cell differentiation back to the normal cells, but little is known about its role in the adhesion of the cell to the extracellular matrix (Fn). We observed that RA increased the ability of NIH3T3 cells to adhere to Fn in a dose-dependent manner. The cell adhesion to fibronectin was promoted by 20% with 32 &mgr;mol/L RA, but not to polylysine. We use anti-integrin alpha(5)-subunit and beta(1)-subunit monoclonal antibodies to measure the amounts of integrin on the cell surface by FCM. It showed that the amounts of alpha(5) and beta(1) subunits of integrin did not change when the NIH3T3 cells were treated with RA for 24 h. But the incorporation of (3)H-mannose was increased by 53 % and those of tri- or tetra- antennary or bisecting complex type oligosaccharides were increased by 13 %. These results indicated that the increased adhesion of the cells to Fn in presence of RA may be caused by altering amounts and types of the oligosaccharides of the glycoprotein on the cell surface.