RRM2B基因复合杂合变异导致的线粒体耗竭综合征家系的临床特征和遗传学分析

目的:探讨1个线粒体DNA耗竭综合征8A型家系的临床特点和致病基因。方法:对患儿进行全外显子测序筛查潜在的基因变异,Sanger测序进行家系验证,并用PolyPhen-2与PROVEAN软件预测氨基酸变异对蛋白功能的影响。结果:患儿,女,2个月4天,临床表现为喂养困难、呼吸急促、肌张力低下等,实验室辅助检查提示患儿发育...     

Contribution of DNA methylation profiling to the reclassification of a variant of uncertain significance in the KDM5C gene

KDM5C encodes a demethylase of the histone H3 lysine 4 residue, involved in chromatin regulation and gene expression. Hemizygous KDM5C pathogenic variants cause X-linked intellectual disability of Claes-Jensen type. Because of its mode of inheritance and the low specificity of the clinical phenotype, interpretation of variants can be difficult, hence the need for functional studies and biomarkers specific to this disorder. We present the case of a male patient with intellectual disability, behavioral abnormalities and subtle dysmorphic features, in which genetic investigation identified a hemizygous novel missense KDM5C variant of uncertain significance (VUS), inherited from his asymptomatic mother and present in his paucisymptomatic sister. We assessed the global genomic DNA methylation status from a whole blood sample of the proband. Global DNA methylation profiling specifically identified the recently discovered epi-signature of Claes-Jensen syndrome. This result served as a biomarker which independently highlighted KDM5C as the cause of the disorder in this patient. Because of the X-linked mode of inheritance, variant reclassification had a high impact on genetic counseling in this family. This example highlights the value of global methylome profiling in situations of variants of uncertain significance in genes with a known specific epi-signature.     

Single base substitutions at the initiator codon in the mitochondrial acetoacetyl-CoA thiolase (ACAT1/T2) gene result in production of varying amounts of wild-type T2 polypeptide

Initiator codon mutations are relatively uncommon and less well characterized compared to other types of mutations. We identified a novel initiator codon mutation (c.2T>C) heterozygously in a Japanese patient (Patient GK30) with mitochondrial acetoacetyl-CoA thiolase (T2) gene deficiency (ACAT1 deficiency); c.149delC was on the other allele. We examined translation efficiencies of nine mutant T2 cDNAs harboring one-base substitutions at the initiator methionine codon using in vivo transient expression analysis. We found that all the mutants produced wild-type T2 polypeptide, to various degrees (wild type (100%) > c.1A>C (66%) > c.2T>C, c.3G>C, c.3G>T (22%) > c3G>A, c.1A>G (11%) > c.2T>A, c.2T>G, c.1A>T (7.4%)). T2 mRNA expression levels in Patient GK08 (a homozygote of c.2T>A) and Patient GK30 fibroblasts, respectively, were almost the same as in control fibroblasts, when examined using semiquantitative PCR. This means that initiator codon mutations did not affect T2 mRNA levels. We propose that all one-base substitutions at the initiator methionine codon in the T2 gene could be mutations, which retain some residual T2 activity.     

怀化地区侗族高血压高发人群醛固酮合成酶基因多态性(-344C/T)研究

目的探讨醛固酮合成酶(CYB11B2)基因多态性与怀化侗族高血压高发人群原发性高血压(EH)及血脂水平的关系.方法采用聚合酶链反应结合限制性内切酶片段长度多态分析方法(PCR-RFLP)检测89例怀化侗族高血压病人和85例正常人的CYB11B2-344C/T等位基因频率和基因型频率.结果高血压组CYB11B2-344C/T基因型频率(CC 10.1%、CT41.6%、TT 48.3%)和等位基因频率(C 30.9%、T 69.1%)与正常对照组基因型频率(CC 10.3%、CT 27.6%、TT 62.1%)和等位基因频率(C 24.1%、T 75.9%)比较无显著性差异.CC基因型患者与CT TT基因型患者比较,收缩压和舒张压无显著性差异.结论怀化侗族人群EH可能与CYB11B2基因多态性无关.     

Cortisol responses to emotional stress in men: association with a functional polymorphism in the 5HTR2C gene

The serotonin 5HTR2C receptor has been shown to mediate HPA axis activation during stress. We hypothesized that a functional polymorphism (rs6318) of the 5HTR2C gene would be associated with HPA axis response to a laboratory stress protocol. The present sample consisted of 41 men (22 African Americans, 19 Caucasians). We found that at rest men with the more active rs6318 Ser23 C allele had similar cortisol values compared to those with the less active Cys23 G allele. During laboratory stress, however, men with the Ser23 C allele exhibited the predicted significantly higher cortisol levels (p < 0.001), as well as larger increases in anger (p = 0.08) and depressive mood (p = 0.006) ratings, compared to the Cys23 G carriers. The increase in cortisol was significantly related to the increases in ratings of anger and depression assessed before and after the emotion induction, and these correlations became nonsignificant when rs6318 genotype was covaried. We conclude that genetic variation in 5HTR2C may be associated with HPA axis activation and stimulated by emotional stress, and also with both psychological and physiological endophenotypes that increase the risk of cardiovascular disease and type-2 diabetes.     

Organisation of the mitochondrial genome of Trichophyton rubrum III. DNA sequence analysis of the NADH dehydrogenase subunits 1, 2, 3, 4, 5 and the cytochrome b gene

In this paper, we present the nucleotide sequence of a 9761 nt-long segment of the mitochondrial genome of the dermatophyte Trichophyton rubrum that bridges the gap between two previously published segments, making a unique contig that represents approximately 80% of the molecule. The location of all genes on the map is determined except for some tRNA genes expected to flank the LSU rRNA gene not yet sequenced. Starting from the 5′ end of the present sequence, we recognized the ND5 and ND2 genes, the cytochrome b gene, an unusually long intergenic spacer of unknown function, as well as the ND3, ND1 and ND4 genes. This sequence extends and confirms the similarity with the mitochondrial genome of Aspergillus nidulans. Interestingly, two cases of partial overlaps between the terminator and initiator codons of successive genes (ND4–ND5 and ND5–ND2) are encountered. Received: 9 July / 10 November 1998