心肌球蛋白重链基因Arg719G1n突变与家族性肥厚型心肌病

目的调查中国人家族性肥厚型心肌病β肌球蛋白重链(β-MHC)基因突变情况,评估中国人肥厚型心肌病临床特点与基因突变的关系.方法对5个独立的肥厚型心肌病家系进行βMI-IC基因突变扫描,通过聚合酶链反应扩增β-MHC基因3～27及40号外显子,通过单链构像多态性及测序检测突变,采用限制性片断长度多态性分析检测其他家系成员.结果发现一家系先证者第19号外显子聚合酶链反应产物单链构象多态性异常,测序分析表明该患者β-MHC基因第719密码子位置发生G→A转换,使精氨酸(Arg)变为谷氨酰胺(Gln).该患者临床表现胸痛、心悸及反复发作晕厥,超声示室间隔轻度不对称肥厚和左房扩大,母亲及姐姐皆有相似临床症状且都已于38岁猝死.此外,在其他4个家系中还发现了位于β-MHC基因上的ACT63ACC、TTT244TIC多态位点,但与疾病无明显相关.结论β-MHC基因Arg719Gln错义突变位于肌球蛋白重链的头杆结合部,该部位系肌球蛋白的重要功能区.该突变表型症状重,发病早,预后差,并与心房扩大和心房纤颤相关,提示该突变是致肥厚型心肌病的恶性突变.另一方面,研究表明同一突变可有不同的临床表现和预后,结合其他4个家系均未发现错义突变的结果,支持肥厚型心肌病的异质性遗传特点.     

心肌球蛋白重链基因Arg719Gln突变与家族性肥厚型心肌病

目的：调查中国人家族性肥厚型心肌病β－肌球蛋白重链（β－MHC）基因突变情况,评估中国人肥厚型心肌病临床特点与基因突变的关系。方法：对5个独立的肥厚型心肌病家系进行β－MHC基因突变扫描,通过聚合酶链反应扩增β－MHC基因3－27及40号外显子,通过单链构像多态性及测序检测突变,采用限制性片断长度多态性分析检测其他家系成员。结果：发现一家系先证第19号外显子聚合酶链反应产物单链构象多态性异常,测序分析表明该患β－MHC基因第719密码子位置发生G→A转换,使精氨酸（Arg)变为谷氨酰胺（Gln)。该患临床表现胸痛,心悸及反复发作晕厥,超声示室间隔轻度不对称肥厚和左房扩大,母亲及姐姐皆有相似临床症状且都已于38岁猝死。此外,在其他4个家系中还发现了位于β－ＭＨＣ基因上的ＡＣＴ６３ＡＣＣ,ＴＴＴ２４４ＴＴＣ多态位点,但与疾病无明显相关。结论：β－ＭＨＣ基因Ａrg719Gln错义突变位于肌球蛋白重链的头杆结合部,该部位系肌球蛋白的重要功能区。该突变表型症状重,发病早,预后差,并与心房扩大和心房纤颤相关,提示该突变是致肥厚型心肌病的恶性突变,另一方面,研究表明同一突变可有不同的临床表现和预后,结合其他４个家系均未发现错义突变的结果,支持肥厚型心肌病的异质性遗传特点。     

Mutations in the cardiac Troponin C gene are a cause of idiopathic dilated cardiomyopathy in childhood

The role of familial disease in childhood dilated cardiomyopathy is unknown. A novel mutation in the cardiac Troponin C gene has been identified recently in a family with dilated cardiomyopathy. Here we present a subsequent case of dilated cardiomyopathy occurring in a child from the same family, and emphasise the implications for future screening and counselling.     

Mutations in low-density lipoprotein receptor gene as a cause of hypercholesterolemia in Taiwan

Familial hypercholesterolemia (FH) is inherited as an autosomal dominant trait that has been associated with more than 920 different mutations in the low-density lipoprotein receptor (LDLR) gene. To characterize LDLR gene mutations in the Chinese of Han descent with FH, we isolated genomic DNA from peripheral blood samples of 20 affected subjects and 50 healthy subjects with no family history of hypercholesterolemia. We used polymerase chain reaction and long polymerase chain reaction to amplify the 18 coding exons and the minimal promoter of the LDLR gene, and subjected amplicons to direct sequence analysis. We identified 6 mutations in LDLR gene, including heterozygous missense mutations I420T (ATC-->ACC), C660W (TGC-->TGG), H562Y (CAC-->TAC), and A606T (GCC-->ACC), and a heterozygous and a homozygous mutation in codon P664L (CCG-->CTG) as well as a homozygous large deletion of exons 6 to 8. The FH homozygotes manifested generalized xanthomatosis. One of the mutations we identified (C660W) was novel. In conclusion, we identified 5 missense mutations and 1 large deletion in LDLR gene, including 1 novel mutation in Han Chinese with FH in Taiwan.     

Clinical characteristics of a familial inherited myxomatous valvular dystrophy mapped to Xq28

OBJECTIVES

The purpose of this study was to describe the phenotypic characteristics of an inherited myxomatous valvular dystrophy mapped to Xq28.

BACKGROUND

Myxomatous valve dystrophies are a frequent cause of valvular diseases, the most common being idiopathic mitral valve prolapse. They form a group of heterogeneous diseases difficult to subclassify. The first mapping of the gene for a myxoid valvular dystrophy to Xq28 allowed investigation of the phenotype of affected members in a large family and characterization of the disease.

METHODS

Among the 318 members in the pedigree, 89 agreed to participate in this study. Phenotypic characteristics were investigated using clinical examination, transthoracic echocardiography and biological analysis (F.VIII activity). Genetic status was based on haplotype analysis.

RESULTS

Among 46 males, 9 were hemizygous to the mutant allele and had an obvious mitral and/or aortic myxomatous valve defect, and 4 had undergone valvular surgery. All had typical mitral valve prolapse associated in six cases with moderate to severe aortic regurgitation. The valve defect cosegregated with mild hemophilia A (F.VIII activity = 0.32 ± 0.05). The 37 remaining males had normal valves and normal F.VIII activity. Heterozygous women were identified on the basis of their haplotypes. Among the 17 women heterozygous to the mutant allele, moderate mitral regurgitation was present in 8, associated with mild mitral valve prolapse in 1 and aortic regurgitation in 3, whereas 2 women had isolated mild aortic regurgitant murmur. In heterozygotes, the penetrance value was 0.60 but increased with age.

CONCLUSION

X-linked myxomatous valvular disease is characterized by mitral valve dystrophy frequently associated with degeneration of the aortic valves affecting males and, to a lower severity, females. The first localization of a gene for myxomatous valvular diseases is the first step for the subclassification of these diseases.     

Oculopharyngeal muscular dystrophy as a cause of dysphagia in the elderly

A case of oculopharyngeal muscular dystrophy in an elderly woman of French-Canadian background presenting with dysphagia is discussed. Typical features of the clinical presentation include bilateral ptosis and dysphagia with significant potential for morbid outcomes of aspiration pneumonia and malnutrition. Although relatively uncommon, this diagnosis should be considered in an elderly person with dysphagia, a history of ptosis, and the proper family background. Surgical treatment appears to improve the signs and symptoms of this disease.     

Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria

Phosphohydroxylysinuria has been described in two patients with neurological symptoms, but the deficient enzyme or mutated gene has never been identified. In the present work, we tested the hypothesis that this condition is due to mutations in the AGXT2L2 gene, recently shown to encode phosphohydroxylysine phospholyase. DNA analysis from a third patient, without neurological symptoms, but with an extreme hyperlaxicity of the joints, shows the existence of two mutations, p. Gly240Arg and p.Glu437Val, both in the heterozygous state. Sequencing of cDNA clones derived from fibroblasts mRNA indicated that the two mutations were allelic. Both mutations replace conserved residues. The mutated proteins were produced as recombinant proteins in Escherichia coli and HEK293T cells and shown to be very largely insoluble, whereas the wild-type one was produced as a soluble and active protein. We conclude that phosphohydroxylysinuria is due to mutations in the AGXT2L2 gene and the resulting lack of activity of phosphohydroxylysine phospholyase in vivo. The finding that the nul alleles of p.Gly240Arg and p.Glu437Val are present at low frequencies in the European and/or North American population suggests that this condition is more common than previously thought. The diversity of the clinical symptoms described in three patients with phosphohydroxylysinuria indicates that this is most likely not a neurometabolic disease.     

Mutations in the sterol 27-hydroxylase gene (CYP27A) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis

Follow-up investigations were undertaken on a previously reported patient who had severe familial giant cell hepatitis in infancy associated with substantially increased urinary excretion of bile alcohol glucuronides. By the age of 11 years, he had developed a profile of cholanoids in plasma and urine that closely resembled the pattern seen in cerebrotendinous xanthomatosis (CTX). Sequencing of the sterol 27-hydroxylase gene (CYP27A) showed that he was homozygous for a deletion (525/526delG) that causes a frameshift and a premature stop codon. This genotype has previously been described in an adult female with classical symptoms of CTX (tendon xanthomata, cataracts and deteriorating cognitive function). A review of past medical histories of a group of patients with CTX revealed that prolonged neonatal cholestatic jaundice was common. The family histories also revealed fetal and neonatal deaths among siblings of patients with CTX. We conclude that defective activity of cholesterol 27-hydroxylase can lead to neonatal cholestatic jaundice ('hepatitis of infancy'), which may be self-limiting. After a latent period, however, progressive accumulation of cholesterol and cholestanol can lead to the xanthomata, neurodegeneration, cataracts and atherosclerosis that are typical of CTX.     

Mutations of the low-density-lipoprotein receptor gene and familial hypercholesterolemia.

Familial hypercholesterolemia (FH), an autosomal dominant disorder caused by mutation of the low-density-lipoprotein (LDL) receptor, occurs in about one in 500 individuals. The evaluation of naturally occurring mutants has permitted an extensive structure-function analysis of this receptor that has provided insight into the biochemistry and cell biology of cell-surface receptors in general. Novel gene therapeutic approaches to the management of FH are a developing outgrowth of this research.     

Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia

Mutations in the ELA2 gene encoding human neutrophil elastase have been reported recently to be involved in the aetiology of both, cyclic (CyN) and congenital neutropenia (CN). We analysed the correlation between the occurrence of ELA2 mutations and the neutropenic phenotype in a family with two children affected with CN. The two children harboured the same heterozygous mutation in the ELA2 gene that was inherited from their unaffected father. We conclude that ELA2 mutations are not the single cause of CN although they might be a necessary prerequisite for the expression of the neutropenic phenotype in a subgroup of CN patients.     

Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an autosomal dominant disorder of lipid metabolism characterized by elevated low-density lipoproteins (LDL), the formation of tendon and skin xanthomata and the development of premature coronary atherosclerosis. It is caused by a defect in the receptor-mediated hepatic uptake of LDL due to mutations in the LDL receptor. In 25 FH families with a total of 160 members and in two individuals without available relatives, all of German origin, we identified LDL receptor mutations by a multiplex-PCR-based single-strand conformation polymorphism method followed by direct sequencing. Of the 24 mutations found, 15 are missense mutations, 2 are nonsense mutations, 4 are small deletions or insertions leading to frameshifts, 2 are an in-frame insertion and deletion, respectively, and one is a splice site mutation. Propositi carrying mutations that are known to completely abolish receptor function (nonsense and frameshift mutations, missense mutation V480M) had significantly higher untreated total and LDL-cholesterol levels compared to those patients carrying missense and in-frame insertion mutations of unknown functional consequence, which may lead to either reduced or completely abolished receptor function (11.30±1.64 vs 9.76±1.50 mmol/L, and 9.39±1.23 vs 7.99±1.45 mmol/L, respectively). These results confirm the clinical and molecular heterogeneity of FH and the influence of different functional classes of mutations on lipid values.     

先天性长QT间期综合征KVLQT1基因新的同义突变位点

目的 :研究中国人先天性长QT间期综合征 (LQTS)患者KVLQT1和HERG基因突变位点。方法 :采用聚合酶链反应和DNA测序对 11个LQTS家系KVLQT1和HERG基因跨膜编码区进行突变检测。结果 :①15例患者在国外已知的突变位点上 ,均未发现有突变。②发现KVLQT1基因 2个新的同义突变 (C6 36T ,G912A) ,位置分别在KVLQT1基因的S4、Pore跨膜片段。结论 :这 2个新的同义突变可能通过影响延迟性整流钾通道的跨膜电流而与LQTS相关