Mutation analysis of Jewish hunter patients in Israel

We have performed molecular and mutation analyses on 14 unrelated Israeli Hunter families and have identified the IDS mutation in 8 of them. Three unrelated Ashkenazi patients had the same previously reported mutation (1246 C→T). Based on the haplotypes of the mutation-bearing chromosomes, we concluded that this is a recurrent mutation. In two patients, we identified a deletion spanning exons V–VII. Three novel mutations were observed in different patients: L410P, 717del4, and 244del3. In addition, the silent mutation (562 C→T) was observed in one patient. © 1994 Wiley-Liss, Inc.     

Codon 178 mutation of the human prion protein gene in a German family (Backer family): sequencing data from 72-year-old celloidin-embedded brain tissue

Familial Creutzfeldt-Jakob disease was first described in a family from northern Germany in the 1920s (Backer family). PCR amplification of DNA extracted from brain tissue embedded in celloidin 72 years ago shows a GAC to AAC substitution at codon 178 of the prion protein gene. This mutation is associated with fatal familial insomnia and familial Creutzfeldt-Jakob disease in a number of families of diverse ethnic background.     

Dysferlin mutation analysis in a group of Italian patients with limb-girdle muscular dystrophy and Miyoshi myopathy

Mutations in the dysferlin gene (DYSF) on chromosome 2p13 cause distinct phenotypes of muscular dystrophy: limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy, which are known by the term 'dysferlinopathy'. We performed mutation analyses of DYSF in 14 Italian patients from 10 unrelated families with a deficiency of dysferlin protein below 20% of the value in normal controls by immunoblotting analysis. We identified 11 different mutations, including eight missense and three deletion mutations. Nine of them were novel mutations. We also identified a unique 6-bp insertion polymorphism within the coding region of DYSF in 15% of Italian population, which was not observed in East Asian populations. The correlation between clinical phenotype and the gene mutations was unclear, which suggested the role of additional genetic and epigenetic factors in modifying clinical symptoms.     

肝豆状核变性ATP7B基因Arg778Leu突变型与临床表现的相关性研究

目的:探讨肝豆状核变性(Hepatolenticular Degeneration,HLD)患者ATP7B基因Arg778Leu突变型与临床表现之间的相关性。方法:采用PCR和DNA测序技术检测91例HLD患者ATPTB基因8号外显子Arg778Leu突变,将91例患者分为纯合突变组、杂合突变组和无突变组,并与临床表现(性别、起病年龄、临床表型)进行相关分析。结果:在91例HLD患者中检出26例Arg778Leu纯合子和40例杂合子,其余25例无此突变。患者性别、起病年龄、临床表型与该突变型均无相关性。结论:Arg778Leu突变与患者性别、起病年龄及临床表型无关。     

石棉相关肿瘤p53基因突变的免疫组化及PCR—SSCP研究

为了分析石棉相关肿瘤ｐ５３基因的突变特点，对石蜡包埋的石棉相关肿瘤ｐ５３基因突变体蛋白的表达进行了免疫组化观察，提取染色体ＤＮＡ，对ｐ５３基因的第５、７、８外显子进行ＰＣＲ－ＳＳＣＰ及测序分析。免疫组化观察发现：在分析的１０例病例中有５例阳性。ＰＣＲ－ＳＳＣＰ分析发现７例（８处）发生突变，其中４处集中在第８外显子上。５例腺癌中有４例发生ｐ５３基因突变。测序发现热点区突变。提示：石棉相关肿瘤ｐ５３基因突变率高。     

A common FGFR3 mutation functions as a diagnostic marker for achondroplasia-group disorders in the Japanese population

Recent DNA studies performed by several groups have detected mutations of the gene encoding fibroblast growth factor receptor 3 (FGFR3) in patients with achondroplasia-group disorders, including achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia (TD). For this study, we analyzed theFGFR3 gene in 31 Japanese patients with typical ACH, four with HCH, three with a condition intermediate between ACH and HCH (ACH/HCH-intermediate), and one with TD. Of the 31 typical ACH patients, 29 showed a G1138 to A transition and the other two a G1138 to C transversion, both resulting in a common Gly380Arg substitution in the transmembrane domain of FGFR3. The one TD and the four HCH patients did not display any mutations in the transmembrane domain of FGFR3. Of the three ACH/HCH-intermediate cases, one patient showed the Gly380Arg substitution and one did not, and further analysis of the second patient revealed the presence of Asn540Lys substitution. The first patient was, therefore, genotypically diagnosed as ACH and the second as HCH. Peripheral blood leukocyte DNA analysis in the remaining ACH/HCH-intermediate patient indicated an unequal ratio of mutant to normal PCR products, possibly representing a somatic mosaic for the Gly380Arg mutation. Analysis of the common FGFR3 mutation thus appears to help in the molecular diagnosis of patients with achondroplasia-group disorders.     

Polycystic kidney disease genes and polycystins

Conclusion The past decade has seen extraordinary progress in the study of autosomal-dominant polycystic kidney disease. The 2 major genes for this disorder have been identified. Animal models of ADPKD have been produced. The molecular basis of the disease has been characterized. ADPKD is a “second-hit” disease, much like many cancer predisposition syndromes. This has profound implications for our understanding. The progression of ADPKD in individual patients is likely related more to their individual rate of acquisition of second hits at thePKD1 orPKD2 locus than to the inherited germ line mutation itself. Therapeutic approaches will perhaps now be considered, which will include interventions that may limit the rate at which somatic mutations occur in the kidney. The major focus of research at present is to elucidate the normal functions ofPKD1 andPKD2. Protein binding partners are being sought for both proteins. The possible calcium channel function ofPKD2 is being investigated. The downstream effects of cellular deficiency of either protein are likely to yield many clues. Modifying genetic factors that may independently affect disease progression are likely to be identified using the several mouse models. Perhaps the next decade will bring great strides in understanding and in potential therapy for this common disease. This paper was presented at the 2nd International Forum “The Frontiers of Nephrology,” Tokyo, May 10, 1998.     

GREB1L基因突变致后天性单侧肾萎缩一例报道并文献复习

肾发育不良和肾发育不全（RAH）是先天性肾脏与尿路畸形（CAKUT）的主要表现之一,是导致儿童慢性肾脏病的重要原因。遗传因素与发病密切相关,随着全基因检测技术的发展,越来越多与RAH相关的基因突变被报道,GREB1L基因突变已被证实可导致RAH。本研究报道了1例后天性单侧肾萎缩GREB1L基因c.4688A>G杂合突变患儿,并复习相关文献。该患儿基因突变源自母亲,该变异为罕见变异,并且具有不完全外显特性,多种蛋白质危害预测软件预测该突变为有害变异。本文发现了新的GREB1L基因突变位点,可能拓展了与RAH相关的基因突变谱和临床谱。