Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype.

Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function. INTRODUCTION: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. MATERIALS AND METHODS: We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. RESULTS: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. CONCLUSION: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships.     

Gitelman综合征SLC12A3基因突变研究

目的分析和确定Gitelman综合征相关基因SLC12A3突变位点,以提高对该病的认识和理解。方法通过直接测序的方法寻找和确定12例Gitelman综合征患者相关基因SLC12A3的突变位点。选取50例健康正常人作为对照,评估发现的突变位点。结果共确定SLC12A3基因8个突变位点,其中5个为新突变位点,包括2个错义突变：Cys430Gly和Leu571Pro;2个缺失突变：1384delG和346～353delACTGATGG;1个非移码插入突变： 997insCys。3个已报道过的突变,其中包括2个错义突变：Thr60Met和Asp486Asn;1个缺失突变：2883-2884delAG。12例患者中8例携带Thr60Met纯合或杂合突变,大部分患者为复合杂合突变。结论基因突变分析对诊断Gitelman综合征有重要价值。Thr60Met可能是中国Gitelman综合征患者较常见的突变。Gitelman综合征特异的表型和基因型之间的联系目前较难确定。     

Clinical implications of mutation analysis in primary hyperoxaluria type 1

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism with an extensive clinical and genetic heterogeneity. Although over 50 disease-causing mutations have been identified, the relationship between genotype and clinical outcome remains unclear. The aim of this study was to determine this association in order to find clues for improvement of patient care. METHODS: AGXT mutation analysis and assessment of biochemical characteristics and clinical outcome were performed on patients from a Dutch PH1 cohort. RESULTS: Thirty-three of a cohort of 57 PH1 patients, identified in The Netherlands over a period of 30 years, were analyzed. Ten different mutations were found. The most common mutations were the Gly170Arg, Phe152Ile, and the 33insC mutations, with an allele frequency of 43%, 19%, and 15%, respectively. Homozygous Gly170Arg and Phe152Ile mutations were associated with pyridoxine responsiveness and a preserved renal function over time when treatment was timely initiated. All patients homozygous for the 33insC mutation had end-stage renal disease (ESRD) before the first year of age. In two unrelated patients, a new Val336Asp mutation was found coupled with the Gly170Arg mutation on the minor allele. We also found 3 patients homozygous for a novel Gly82Arg mutation with adverse outcome in 2 of them. CONCLUSION: Early detection of Gly170Arg and Phe152Ile mutations in PH1 has important clinical implications because of their association with pyridoxine responsiveness and clinical outcome. The association of a homozygous 33insC mutation with severe infantile ESRD, resulting in early deaths in 2 out of 3 cases, warrants a choice for prenatal diagnostics in affected families.     

Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli

OBJECTIVE: Using an interdisciplinary clinical and molecular approach, the authors identified APC germline mutations in families with familial adenomatous polyposis (FAP). Correlation of mutation site with disease manifestation and the impact of molecular data on clinical proceedings were examined. SUMMARY BACKGROUND DATA: Germline mutations in the APC gene predispose to FAP. Established and proposed genotype-phenotype correlations as well as the influence of mutation site on surgical procedures have been reported. The predictive value of APC mutation analysis for disease manifestation and therapeutic decision making needs to be investigated further. METHODS: One hundred twenty-three kindreds of the local FAP registry were included in this study. CHRPE phenotype was defined as at least one large characteristic lesion or a total of four lesions in both eyes. APC mutations were identified by protein truncation test and automated DNA sequencing from patient lymphocyte DNA and RNA. RESULTS: APC germline mutations were identified in 85/123 families with FAP. They were located between codons 213 and 1581 of the APC gene and displayed distinct genotype-phenotype correlations. CHRPE status facilitated mutation analysis by discriminating regions of interest within the APC coding region. Severe manifestations of desmoids were restricted to mutations between codons 1444 through 1581. Whereas 91% (75/82) of at-risk persons were excluded as mutation carriers, APC germline mutations were detected before clinical examination in 9% (7/82) of at-risk persons. One patient agreed to endoscopy only after mutation detection. CONCLUSIONS: This study supports the feasibility of combined molecular and clinical screening of families with FAP and may provide a guideline for routine presymptomatic molecular diagnostics in a clinical laboratory.     

NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence

BACKGROUND: Mutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations. METHODS: NPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS). RESULTS: Twenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases. CONCLUSION: Patients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation.     

Prevalence of mutations in AGPAT2 among human lipodystrophies

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.     

Genetic analysis of Gitelman syndrome patients from the Czech Republic and Slovakia--three novel mutations found

BACKGROUND: To investigate the genetic cause of inherited hypokalemic metabolic alkalosis associated with Gitelman's syndrome, we searched for mutations in the SLC12A3 gene (thiazide-sensitive NaCl cotransporter) among a set of patients from the Czech Republic and Slovakia. METHODS: We collected blood samples of patients from 16 families with characteristic clinical features. DNA was analyzed for mutation detection with SSCP and subsequent sequencing. Several mutations might be missed when only the SSCP method is applied, therefore direct sequencing of all the 26 exons became an essential tool. RESULTS: Genetic analysis revealed mainly missense mutations. Two novel mutations, c.480dupC (p.Pro160fsX97) and c.238dupCC (p. Pro79fsX35), caused a frameshift and preliminary stop codon appearance. Missense mutation c.790 G --> C (p.Gly264Arg) has never been reported before. Mutation c.1315G --> A (p.Gly439Ser) was frequent among our collection of unrelated patients (5 out of 16). Homozygous Gly439Ser was observed in a patient with chondrocalcinosis. CONCLUSION: We identified 13 different causative mutations in a cohort of Gitelman syndrome patients. Three of those mutations are novel. The occurrence of two mutation detections per individual corresponding to a recessive trait of inheritance was 62.5%. Gly439Ser is the most frequent type of mutation among our patients. Statistic evaluation of genotype/phenotype correlation could not be carried out.     

Cystic fibrosis mutations and genotype-pulmonary phenotype analysis.

BACKGROUND: Although there are more than 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, most of them are uncommon and only limited information exists regarding genotype-pulmonary phenotype relationships. METHODS: We determined and classified the CFTR mutations using denaturing high-performance liquid chromatography and developed new, quantitative methods to categorize pulmonary phenotypes. RESULTS: Two novel alleles were discovered, namely G1047R and 1525-2A-->G, which were accompanied by F508del and G551D mutations, respectively. Assessment of numerous options revealed that CF pulmonary phenotype categorization in children cannot be accomplished with clinical or pulmonary function data but is facilitated by longitudinal quantitative chest radiology. It was most useful to categorize pulmonary disease status by evaluating the typical pattern of abnormalities in patients homozygous for the F508del mutation, and then compare patients with minor mutations to this typical CF pulmonary phenotype. By this method, both patients with novel mutations have pulmonary phenotypes typical of F508del homozygotes. However, patients with class IV mutations (e.g., R347P) or with pancreatic sufficiency showed serial chest radiographs that were atypically mild. CONCLUSIONS: Longitudinal quantitative chest radiography provides a new strategy for CF pulmonary phenotype categorization that should be useful for genotype-phenotype delineation in individual patients and in both epidemiologic studies and clinical trials involving groups of children with CF.     

Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome

Mutations in the gene encoding podocin (NPHS2) cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). For addressing the possibility of a genotype-phenotype correlation between podocin mutations and age of onset, a worldwide cohort of 430 patients from 404 different families with SRNS were screened by direct sequencing. Recessive podocin mutations were present in 18.1% (73 of 404) of families with SRNS, and 69.9% of these mutations were nonsense, frameshift, or homozygous R138Q. Patients with these mutations manifested symptoms at a significantly earlier age (mean onset <1.75 years) than any other patient group, with or without podocin mutations, in this study (mean onset >4.17 yr). All but one patient affected by truncating or homozygous R138Q mutations developed SRNS before 6 yr of age. Patient groups with other recessive podocin mutations, with single heterozygous podocin mutations, with sequence variants, and with no podocin changes could not be distinguished from each other on the basis of age of onset. In conclusion, nephrotic syndrome in children with truncating or homozygous R138Q mutations manifests predominantly before 6 yr of life, and the onset of disease is significantly earlier than for any other podocin mutations. Because the age of onset can vary by several years among those with identical mutations, additional factors may modify the phenotype.     

Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations

OBJECTIVE: To describe a genotype-phenotype correlation in MEN2 families with germline mutations of codons 790/791 and discuss options for the therapeutic management of gene carriers. SUMMARY BACKGROUND DATA: Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the protooncogene. Rare mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC phenotype were reported in five families, contraindicating the prophylactic thyroidectomy for the genetically affected children. METHODS: Forty-five patients with a putative sporadic MTC were screened for germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemically, and all gene carriers underwent prophylactic thyroidectomy. RESULTS: Five index patients were identified, four of whom harbored mutations in codons 790/791 and one in codon 634. In the kindreds, four L790F carriers and one Y791F carrier were detected. The thyroid gland histology of L790F carriers revealed medullary thyroid carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two additional patients (aged 9 and 16 years). The Y791F carrier had a normal histology. CONCLUSIONS: Codon 790/791 mutations had diverse penetrance. Whereas prophylactic thyroidectomy in children is a justifiable approach for codon 790 mutation carriers, the indication for thyroidectomy should depend on the clinical course of codon 791 carriers.     

A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies

BACKGROUND: Gitel syndrome is an inherited tubular disorder characterized by metabolic alkalosis, hypokalemia, and hypomagnesemia of renal origin and hypocalciuria. The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule. The purpose of this study was to investigate the underlying mutation in Gitelman syndrome patients of Gypsy race from different geographic origin. METHODS: Twenty Gypsy patients with clinical and biochemical features of Gitelman syndrome were investigated by mutational analysis. The patients belonged to 12 unrelated Gypsy families living in four different European countries. The parents and unaffected siblings of each patient, as well as the DNA of a population of 200 healthy control patients, were also analyzed. RESULTS: All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene. This mutation was not found in the control population. Parents were heterozygous for the mutation. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms in six children to severe growth retardation in four. CONCLUSION: Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. This finding will facilitate the identification of the genetic defect in further cases of Gitelman syndrome among the Gypsy population. Our study represents the largest series ever published of patients with Gitelman syndrome having the same underlying mutation, and supports the lack of correlation between genotype and clinical phenotype in this disease.     

Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling.

BACKGROUND: Alport syndrome (AS) is a hereditary nephropathy characterized by progressive renal failure, hearing loss and ocular lesions. Numerous mutations of the COL4A5 gene encoding the alpha 5-chain of type IV collagen have been described, establishing the molecular cause of AS. The goal of the present study was to identify the genotype-phenotype correlations that are helpful in clinical counseling. COL4A5-mutations (n=267) in males were analysed including 23 German Alport families. METHODS: Exons of the COL4A5 gene were PCR-amplified and screened by Southern blot, direct sequencing or denaturing gradient gel electrophoresis. Phenotypes were obtained by questionnaires or extracted from 44 publications in the literature. Data were analysed by Kaplan-Meier statistics, chi(2) and Kruskal-Wallis tests. RESULTS: Genotype-phenotype data for 23 German Alport families are reported. Analysis of these data and of mutations published in the literature showed the type of mutation being a significant predictor of end-stage renal failure (ESRF) age. The patients' renal phenotypes could be grouped into three cohorts: (1) large rearrangements, frame shift, nonsense, and splice donor mutations had a mean ESRF age of 19.8+/-5.7 years; (2) non-glycine- or 3' glycine-missense mutations, in-frame deletions/insertions and splice acceptor mutations had a mean ESRF age of 25.7+/-7.2 years and fewer extrarenal symptoms; (3) 5' glycine substitutions had an even later onset of ESRF at 30.1+/-7.2 years. Glycine-substitutions occurred less commonly de novo than all other mutations (5.5% vs 13.9%). However, due to the evolutionary advantage of their moderate phenotype, they were the most common mutations. The intrafamilial phenotype of an individual mutation was found to be very consistent with regards to the manifestation of deafness, lenticonus and the time point of onset of ESRF. CONCLUSIONS: Knowledge of the mutation adds significant information about the progress of renal and extrarenal disease in males with X-linked AS. We suggest that the considerable prognostic relevance of a patient's genotype should be included in the classification of the Alport phenotype.     

APC genotype, polyp number, and surgical options in familial adenomatous polyposis.

OBJECTIVE: This study was performed to examine the relation between phenotypic expression in patients with familial adenomatous polyposis (FAP) and the site of mutations in the APC (adenomatous polyposis coli) gene. The ability of APC mutations to predict surgical outcome was also investigated. SUMMARY BACKGROUND DATA: Germline mutations in the APC gene cause FAP and can now be identified by direct mutational analysis. Such an analysis can identify affected persons for close surveillance and spare unaffected persons. Phenotypic expression varies within and among FAP kindreds, but certain mutations have been associated with severe disease. Patients with severe polyposis are frequently offered total proctocolectomy rather than colectomy and ileorectal anastomosis out of concern for increased rectal cancer risk. Mutation analysis may offer a more rational basis for these decisions. METHODS: The postsurgical courses of 58 patients from 19 FAP kindreds with identified APC gene mutations were reviewed. APC gene mutations were identified by analysis of leukocyte DNA using single-strand conformational analysis and DNA sequencing. FAP severity was defined according to the number of polyps in the colon at the time of resection (< 1000, mild; > 1000, severe). Operations included subtotal colectomy with ileorectal anastomosis (IRA), total proctocolectomy with ileal pouch/anal anastomosis, total proctocolectomy with end ileostomy, and partial colectomy (PC). RESULTS: Eight different APC mutations were identified. Mutations at codons 1309 and 1328 in exon 15G were associated with a uniformly severe polyposis phenotype. For other mutations, the phenotype was more variable. Patients with APC mutations at codons 1309 and 1328 more commonly underwent proctectomy. Among the 43 patients who initially underwent either IRA or PC, the rectum was later removed in 8. Seven of these patients had a mutation at codon 1309 or 1328. With one exception, all patients with mutations outside the 1309 or 1328 site who initially had IRA have retained their rectum. CONCLUSIONS: Our data support an association between severe polyposis phenotype and mutations at APC gene codons 1309 and 1328. For patients with these mutations, the prognosis for retaining the rectum is poor.     

Mutations of the cationic trypsinogen gene in patients with hereditary pancreatitis

BACKGROUND: Hereditary pancreatitis has been shown to be caused by one of two mutations (R117H and N21I) of the cationic trypsinogen gene (PRSS1). Families with hereditary pancreatitis in the north of England were investigated for these mutations. The clinical features associated with each mutation were compared. METHODS: In individuals from nine families with hereditary pancreatitis, DNA was screened for the R117H and N21I mutations. All five exons of the cationic trypsinogen gene were also sequenced to search for additional mutations. Haplotype analysis was carried out to identify common ancestors. Clinical data were collected. RESULTS: The R117H mutation was identified in three families and N21I in a further five. The R117H mutation was associated with a more severe phenotype than N21I in terms of mean(s.d.) age of onset of symptoms (8.4(7.2) versus 16. 5(7.1) years; P = 0.007) and requirement for surgical intervention (eight of 12 versus four of 17 patients respectively; P = 0.029). Haplotype analysis suggested that each mutation had arisen more than once. CONCLUSION: Two mutations in the cationic trypsinogen gene cause hereditary pancreatitis in eight of nine families originating in this region. The R117H mutation is associated with a more severe form of the disease in terms of age at onset of symptoms and requirement for surgical intervention.     

Genotype–phenotype relationship for five CFTR mutations frequently identified in western France

BACKGROUND: Cystic fibrosis (CF) is the most common inherited disorder in Caucasian populations, with more than 1000 cystic fibrosis transmembrane conductance regulator (CFTR) mutations presently described. The distribution of the mutations ranges widely between countries and/or ethnic groups. Multicentric studies are usually needed to study the genotype-phenotype correlations. METHODS: Since 1992, the French CF Registry (FCFR) has collected and analyzed data from most of the CF patients regularly seen in CF care centres in France. We compared the mutation distribution of the patients born in western France to that of those born elsewhere in France. Then we extracted the available data for all the compound heterozygotes carrying the DeltaF508 allele and one of the following mutations: DeltaI507, 1078delT, 4005+1G->A, E60X and W846X, and matched a patient homozygous for the DeltaF508 mutation for each of them. RESULTS: Western France appeared to have a specific distribution of some CF mutations. Furthermore, disparities were found regarding the mutation repartition (DeltaI507 in Normandy, 1078delT, 4005+1G->A and W846X in western Brittany). Genotype-phenotype correlations showed a wide heterogeneity. Although variations were found, DeltaI507/DeltaF508, 4005+1G->A/DeltaF508 and 1078delT/DeltaF508 patients appeared to have a similar disease as the DeltaF508/DeltaF508 patients. Although the W846X and E60X mutations should be considered as severe alleles as regards to pancreatic function, they were associated with less severe pulmonary manifestations and, probably, better prognosis. CONCLUSION: The knowledge of the distribution of uncommon CF mutations specific to particular areas and of their associated phenotype makes up an essential tool in the management of local CF patients.     

Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Spondyloocular syndrome is an autosomal‐recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730*) in a female patient. The patient presents visual impairment, generalized osteoporosis, short stature with short trunk, spinal compression fractures, and increased intervertebral disc space and hearing loss. We extended our XYLT2 analysis to a cohort of 22 patients with generalized osteoporosis, mostly from consanguineous families. In this cohort, we found by Sanger sequencing 2 siblings and 1 single patient who were homozygous for missense mutations in the XYLT2 gene (p.Arg563Gly and p.Leu605Pro). The patients had osteoporosis, compression fractures, cataracts, and hearing loss. Bisphosphonate treatment in 1 patient resulted in almost complete normalization of vertebral structures by adolescence, whereas treatment response in the others was variable. This report together with a previous study shows that mutations in the XYLT2 gene result in a variable phenotype dominated by spinal osteoporosis, cataract, and hearing loss. © 2016 American Society for Bone and Mineral Research.     

The Wilms tumour gene, WT1, in normal and abnormal nephrogenesis

The Wilms tumour gene, WT1, has been shown to play an important role in normal development of the kidney and gonad. Constitutional mutations predispose to both malformation and childhood tumours of these organs. There is a genotype-phenotype correlation, with missense mutations producing more severe abnormalities than complete absence of one allele. Two syndromes with early-onset protein-losing nephropathy can be distinguished according to the type of WT1 mutation. Children with apparently isolated diffuse mesangial sclerosis may also be WT1 mutation carriers. WT1 is not the major gene mutated in Wilms tumour, but has given important insights into the molecular genetics of this childhood embryonal kidney cancer. Recommendations for management of children suspected of having a WT1 mutation are discussed. Received: 2 September 1998 / Revised: 30 October 1998 / Accepted: 4 November 1998     

常染色体隐性遗传性远端肾小管酸中毒患儿ATP6V0A4和ATP6V1B1基因突变分析

目的 分析常染色体隐性遗传性远端肾小管酸中毒(rdRTA)患儿ATP6V0A4和ATP6V1B1基因的突变,进行基因型和表型的相关性研究.方法 PCR扩增基因组DNA,直接测序分析来自3个家系3例患儿的ATP6V0A4和ATP6V1B1基因的突变位点,选取不相关的100例健康人作为对照.结果 1例患儿携带ATP6V0A4基因的1个新的纯合无义突变(p.R194X);1例患儿携带ATP6V1B1基因1个新的杂合无义突变(p.R114X)和1个已经报道过的杂合突变p.I386fsX441;第3例患儿未发现以上2个基因的突变.结论 对中国rdRTA患者基因突变分析有利于了解该类疾病的基因型和表型的相关性,增强临床医生对该类疾病的认识和治疗.