Features of a Chinese family with cerebral cavernous malformation induced by a novel CCM1 gene mutation / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Familial cerebral cavernous malformations (CCMs), characterized by hemorrhagic stroke, recurrent headache and epilepsy, are congenital vascular anomalies of the central nervous system. Familial CCMs is an autosomal dominant inherited disorder and three CCM genes have been identified. We report a Chinese family with CCMs and intend to explore clinical, pathological, magnetic resonance imaging (MRI) features and pathogenic gene mutation of this family.</p><p><b>METHODS</b>Totally 25 family members underwent brain MRI examination and clinical check. Two patients with surgical indications had surgical treatment and the specimens were subjected to histopathological and microstructural examination. In addition, polymerase chain reaction (PCR) and direct sequencing were performed with genomic DNA extracted from 25 family members' blood samples for mutation detection.</p><p><b>RESULTS</b>Brain MRI identified abnormal results in seven family members. All of them had multiple intracranial lesions and four cases had skin cavernous hemangioma. T2-weighted sequence showed that the lesions were typically characterized by an area of mixed signal intensity. Gradient-echo (GRE) sequence was more sensitive to find micro-cavernous hemangiomas. There was a wide range in the clinical manifestations as well as the age of onset in the family. The youngest patient was an 8-year-old boy with least intracranial lesions. Histopathological and microstructural examination showed that CCMs were typically discrete multi-sublobes of berry-like lesions, with hemorrhage in various stages of illness evolution. They were formed by abnormally enlarged sinusoids and the thin basement membranes. A novel T deletion mutation in exon 14 of CCM1 gene was identified by mutation detection in the seven patients. But unaffected members and healthy controls did not carry this mutation.</p><p><b>CONCLUSIONS</b>The clinical manifestations were heterogenic within this family. We identified a novel mutation (c.1396delT) was the disease-causing mutation for this family and extended the mutational spectrum of CCMs.</p>

Association of two SNPs in 3'UTR of ETS1 gene with systemic lupus erythematosus in a northern Chinese Han population / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association between 2 single nucleotide polymorphisms (SNPs) of ETS1 gene and susceptibility to systemic lupus erythematosus (SLE) in a northern Chinese Han population.</p><p><b>METHODS</b>Two SNPs within the ETS1 gene mapped to 11q23 were selected based on HapMap data. Genotyping was conducted with Taqman method in 231 patients with SLE and 474 healthy controls from Qilu Hospital, Shandong and analyzed with PLINK1.07 software. Haplotypes were analyzed with SHEsis software.</p><p><b>RESULTS</b>A statistically significant difference was detected in the distribution of rs1128334 and rs4937333 genotypes between the two groups (all P< 0.01). For rs1128334, the frequency of the minor allele was 0.291 and 0.428 in controls and cases, respectively. For rs4937333, the minor allele frequency was 0.381 and 0.476 in controls and cases respectively. An A-C haplotype was found to be strongly associated with increased risk for SLE, while another haplotype G-C may reduce this risk.</p><p><b>CONCLUSION</b>Our study has suggested that rs1128334 and rs4937333 are strongly associated with the risk for SLE in northern Chinese Han population.</p>

Association of common polymorphisms in the LRP6 gene with sporadic coronary artery disease in a Chinese population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Genetic factors contribute to the development of coronary artery disease (CAD). Recently, a missense mutation in the low density lipoprotein receptor related protein 6 (LRP6) gene, encoding low density lipoprotein receptor related protein 6, has been implicated in an autosomal dominant form of early-onset CAD. The aim of this study was to determine whether the common variants in LRP6 are associated with sporadic CAD in Chinese.</p><p><b>METHODS</b>A total of 766 CAD patients and 806 healthy controls were included in this study. The presence of angiographic CAD was determined by coronary angiographic analysis. Six signal nucleotide polymorphisms (SNPs) were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.</p><p><b>RESULTS</b>A significant association was detected between rs11054731 in LRP6 intron 2 and CAD in our cohort (P = 0.001). The CC genotype and C allele frequency in the case group were 52% and 72%. Using a dominant model of inheritance, the C allele of rs11054731 was shown to be an independent risk factor for CAD with an OR of 1.45 (95%CI: 1.19 - 1.77, P = 0.0002). With the stratification according to the number of affected coronary arteries, an association was observed between rs11054731 and CAD (P = 0.0002). No significant association was observed between any other SNPs and the risk of CAD.</p><p><b>CONCLUSION</b>The C allele of the rs11054731 within the LRP6 gene was associated with increased risk and extent of CAD in Chinese.</p>

Association of the ABCG1 gene polymorphism with the susceptibility and severity of coronary atherosclerotic disease / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the association of the ATP-binding cassette sub-family G member 1 (ABCG1) gene polymorphisms with coronary atherosclerotic disease (CAD) in Chinese Han population.</p><p><b>METHODS</b>A population based case-control association study was carried out in 541 patients with CAD and 649 healthy controls from Chinese Han population. Two single nucleotide polymorphisms (SNPs) of the ABCG1 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Logistic regression was used to compare the genotypic and allelic frequency difference.</p><p><b>RESULTS</b>The frequency of allele C of rs225374 was significantly higher in the CAD patients than that in the healthy controls (OR=1.186, 95%CI: 1.009-1.394, P=0.039), while the difference was also significant in the male subgroup (OR=1.236, 95%CI: 1.014-1.506, P=0.036). A statistically higher frequency of rs1044317 allele A was found in the CAD patients in comparison to the healthy controls (OR=1.187, 95%CI: 1.009-1.397, P=0.039). In case-only association study, rs225374 showed significant association in the high Gensini score group compared with the low Gensini score group (OR=1.303, 95%CI: 1.024-1.657, P=0.031).</p><p><b>CONCLUSION</b>The two SNPs of the ABCG1 gene might be associated with the susceptibility and severity of CAD in Chinese Han population.</p>

Association of rs2298212 polymorphism in OX40 gene with coronary atherosclerotic disease in Chinese Han population / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study the association of the OX40 gene rs2298212G/A polymorphism with coronary atherosclerotic disease (CAD) in Chinese Han population.</p><p><b>METHODS</b>Five hundred and thirty six CAD patients and 544 age and ethnic matched controls of Chinese Han population were recruited from Qilu Hospital, Shandong University. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype the selected single nucleotide polymorphism. Distributions of genotypic and allelic frequencies were analyzed by Chi-square test.</p><p><b>RESULTS</b>The distribution of genotypic and allelic frequencies have no significant differences between the CAD cases and controls(P> 0.05), even after adjusting for age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glucose, total cholesterol, and triglyceride. However, when substratification analysis of the involved coronary artery vessels was performed, significant difference was found between single-vessel and triple-vessel (P= 0.02, OR = 1.56, 95% CI: 1.08-2.26) involvement.</p><p><b>CONCLUSION</b>The rs2298212G/A polymorphism in OX40 gene may be associated with the severity of coronary atherosclerotic disease.</p>

Clinical investigation of a family with brachydactyly type A1 and the identification of the disease gene / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To determine the inheritance mode and pathogenesis of a family with brachydactyly type A1 in Jining, Shandong province via clinical feature and disease gene analysis.</p><p><b>METHODS</b>Family survey and clinical examinations were performed to determine the inheritance mode; microsatellite polymorphic markers and polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)were employed for linkage analysis and mutation screening respectively.</p><p><b>RESULTS</b>The brachydactyly type of the family was type A1 (BDA1), and autosomal dominant inheritance. A missense mutation (G298A) of the indian hedgehog gene (IHH) was identified in the patients of this family.</p><p><b>CONCLUSION</b>A missense mutation G298A of the IHH gene might be the molecular basis for the brachydactyly type A1 in this family from Shandong province.</p>

N-ras and fms gene mutation in idiopathic thrombocytopenic purpura and myelodysplasia / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the pathogenesis of idiopathic thrombocytopenic purpura (ITP) and improve the differential diagnosis from myelodysplastic syndromes (MDS).</p><p><b>METHODS</b>Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was performed to detect the point mutation of codon 12,13 in N-ras gene and codon 301, 969 in fms gene in adult and aged ITP and MDS patients.</p><p><b>RESULTS</b>In 25 ITP patients, N-ras mutation and fms mutation were detected in one each (4%). Mutations were found in 3 of 8 MDS patients: two (25%) with N-ras mutation and one (12.5%) with fms mutation.</p><p><b>CONCLUSIONS</b>Patients with N-ras or fms gene mutation diagnosed as MDS rather than ITP.</p>

Analysis on genetic polymorphism of 5 STR loci selected from X chromosome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To select short tandem repeats(STR) from X chromosome.</p><p><b>METHODS</b>STR is a universal genetic marker that has changeable polymorphism and stable heredity in human genome. It is a specific DNA segment composed of 2-6 base pairs as its core sequence. It is an ideal DNA marker used in linkage analysis and gene mapping. In this study, 8 short tandem repeats were selected from two genomic clones on X chromosome by using BCM Search Launcher. Primers amplifying the STR loci were designed by using Primer 3.0 according to the unique sequence flanking the STRs. Polymorphisms of the short tandem repeats in Chinese population were evaluated by PCR amplification and PAGE.</p><p><b>RESULTS</b>Five of these STRs were polymorphic. Chi-square test indicated that the distribution of genotypes agreed with Hardy-Weinberg equilibrium (P>0.05).</p><p><b>CONCLUSION</b>Five polymorphic short tandem repeats have been identified on chromosome X and will be useful for linkage analysis and gene mapping.</p>

Fine mapping of Smith-Fineman-Myers syndrome and exclusion of GPC3, GPCR2 MST4 and GLUD2 as candidate genes / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>Smith-Fineman-Myers syndrome (SFMS) is an X-linked mental retardation syndrome. The authors had ascertained a large Chinese family with SFMS from Shandong and had mapped the disease locus to an interval of 19.8 Mb on Xq25 flanked by markers DXS8064 and DXS8050. Further investigation suggested that SFMS exhibited locus heterogeneity. In this study for facilitating the identification of the gene responsible for SFMS, the additional markers were analyzed to narrow down the candidate region, and four candidate genes (GPC3, MST4,GPCR2 and GLUD2) were chosen and screened for disease-causing mutation.</p><p><b>METHODS</b>PCR and denaturing polyacrylamide gel electrophoresis were used to genotype 13 new polymorphic markers distributed within the candidate region. Mutation detection was accomplished by sequencing the exons and intron-exon junctions of the candidate genes.</p><p><b>RESULTS</b>By analyzing 13 additional polymorphic markers, SFMS candidate region can be reduced to an interval of 10.18 Mb bounded by XSTR3 and XSTR4, and no disease-causing mutation was identified in the coding regions of four candidate genes.</p><p><b>CONCLUSION</b>GPCR2 GPC3, MST4 and GLUD2 were excluded as pathogenic genes for SFMS. The refined SFMS locus will assist in the identification and characterization of other candidate genes for SFMS.</p>

Application of homozygosity mapping to the fine mapping of the osteoporosis-pseudoglioma syndrome locus / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To evaluate the role of homozygosity mapping in the fine mapping of the genes responsible for the rare autosomal recessive diseases.</p><p><b>METHODS</b>Polymerase chain reaction-single sequence length polymorphism was used to genotype the family members from 8 families with osteoporosis-pseudoglioma syndrome(OPS) for 14 polymorphic loci within candidate region. The OPS candidate region was narrowed by searching for homozygous region in affected.</p><p><b>RESULTS</b>The OPS candidate region was narrowed to a 1 cM interval between D11S1296 and D11S4136.</p><p><b>CONCLUSION</b>Homozygosity mapping is a powerful method for mapping and narrowing the candidate region of the genes responsible for the rare autosomal recessive diseases.</p>