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Michael P Whyte - One of the best experts on this subject based on the ideXlab platform.
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elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers schonberg disease chloride channel 7 deficiency osteopetrosis among the sclerosing bone disorders
Journal of Bone and Mineral Research, 2010Co-Authors: Lydia G Kempa, Steven Mumm, Michael P Whyte, William H. Mcalister, Fan Zhang, Deborah WenkertAbstract:Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schonberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency. © 2010 American Society for Bone and Mineral Research.
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elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers schonberg disease chloride channel 7 deficiency osteopetrosis among the sclerosing bone disorders
Journal of Bone and Mineral Research, 2010Co-Authors: Lydia G Kempa, Steven Mumm, Michael P Whyte, William H. Mcalister, Fan Zhang, Deborah WenkertAbstract:Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schonberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency.
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albers schonberg disease autosomal dominant osteopetrosis type ii results from mutations in the CLCN7 chloride channel gene
Human Molecular Genetics, 2001Co-Authors: Erna Cleiren, Michael P Whyte, Jens Bollerslev, Jeppe Gram, O Benichou, Frederick R Singer, Katherine L Beaverson, Alexander Aledo, Tatsuo Yoneyama, Mariechristine DevernejoulAbstract:: Albers-Schonberg disease, or autosomal dominant osteopetrosis, type II (ADO II), is the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption. Following the assignment of the gene causing ADO II to chromosome 16p13.3, we now report seven different mutations in the gene encoding the CLCN7 chloride channel in all 12 ADO II families analysed. Additionally, a patient with the severe, autosomal recessive, infantile form of osteopetrosis (ARO) was identified as being homozygous for a CLCN7 mutation. From genotype-phenotype correlations, it seems that ADO II reflects a dominant negative effect, whereas loss-of-function mutations in CLCN7 do not cause abnormalities in heterozygous individuals. Because some ARO patients have mutations in both copies of the CLCN7 gene, ADO II is allelic with a subset of ARO cases.
Deborah Wenkert - One of the best experts on this subject based on the ideXlab platform.
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elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers schonberg disease chloride channel 7 deficiency osteopetrosis among the sclerosing bone disorders
Journal of Bone and Mineral Research, 2010Co-Authors: Lydia G Kempa, Steven Mumm, Michael P Whyte, William H. Mcalister, Fan Zhang, Deborah WenkertAbstract:Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schonberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency. © 2010 American Society for Bone and Mineral Research.
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elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers schonberg disease chloride channel 7 deficiency osteopetrosis among the sclerosing bone disorders
Journal of Bone and Mineral Research, 2010Co-Authors: Lydia G Kempa, Steven Mumm, Michael P Whyte, William H. Mcalister, Fan Zhang, Deborah WenkertAbstract:Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schonberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency.
Steven G Waguespack - One of the best experts on this subject based on the ideXlab platform.
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autosomal dominant osteopetrosis clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Steven G Waguespack, Linda A Dimeglio, Michael J EconsAbstract:Context: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (CLCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. Objectives: The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date. Design and Setting: This study was primarily a retrospective cross-sectional analysis of individuals with a CLCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied. Patients and Interventions: We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistries), 32 unaffected gene carriers (subjects with the gene mutation b...
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analysis of variation in expression of autosomal dominant osteopetrosis type 2 searching for modifier genes
Bone, 2005Co-Authors: Kang Chu, Steven G Waguespack, Daniel L Koller, Tonya Fishburn, Tatiana Foroud, Richard Snyder, Dongbing Lai, Michael J EconsAbstract:Abstract Introduction: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the CLCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66%, with a highly variable phenotype. Methods: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the CLCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal CLCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the CLCN7 gene might influence disease expression. Results: We found potential evidence of linkage for a modifier gene(s) on 9q21–22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type CLCN7 sequence, 94.92% (56/59) of clinically affected subjects and 78.13% (25/32) of unaffected gene carriers had a valine while 5.08% (3/59) of the affected subjects and 21.88% (7/32) of unaffected gene carriers had a methionine ( P P Conclusions: Chromosome 9q21–22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.
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osteoclast derived serum tartrate resistant acid phosphatase 5b in albers schonberg disease type ii autosomal dominant osteopetrosis
Clinical Chemistry, 2004Co-Authors: Sari L Alatalo, Steven G Waguespack, Michael J Econs, Kaisa K Ivaska, Kalervo H Vaananen, Jussi M HalleenAbstract:Background: Albers-Schonberg disease, or autosomal dominant osteopetrosis type II (ADO2), is caused by ineffective osteoclastic bone resorption resulting from mutations in the chloride channel 7 ( CLCN7 ) gene. Individuals with ADO2 have increased numbers of large ineffective osteoclasts in addition to increased serum total tartrate-resistant acid phosphatase (TRACP) activity. Methods: We investigated the serum activity of the osteoclast-derived 5b isoform of TRACP (TRACP 5b) and concentrations of the bone formation marker osteocalcin in clinically affected individuals, unaffected gene carriers, and healthy controls from 10 ADO2 families with known CLCN7 gene mutations. Bone fracture prevalence was studied in association with the serum markers. Results: Similar to total TRACP, TRACP 5b was significantly increased in clinically affected individuals compared with age-matched controls. TRACP 5b correlated significantly with total TRACP ( r = 0.833; P <0.001), suggesting that most of the TRACP in the serum of ADO2 patients is osteoclast-derived TRACP 5b. Osteocalcin was significantly increased in affected adults and slightly decreased in affected children. TRACP 5b and total TRACP were significantly increased in clinically affected individuals with severe fractures ( P <0.05). Conclusions: The results indicate that in ADO2, serum TRACP 5b reflects the number of osteoclasts and that the extremely high serum TRACP 5b activity is a specific indicator of the disease. Similar to total TRACP, TRACP 5b appears to be a potentially useful marker to stratify individuals with CLCN7 gene mutations into clinically affected and unaffected gene carriers. It may also have a prognostic value in the prediction of fractures in patients with a CLCN7 gene mutation.
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chloride channel 7 CLCN7 gene mutations and autosomal dominant osteopetrosis type ii
Journal of Bone and Mineral Research, 2003Co-Authors: Steven G Waguespack, Daniel L Koller, Kenneth E White, Tonya Fishburn, Gwenaelle Carn, Kenneth A Buckwalter, Michelle L Johnson, Maureen Kocisko, Wayne E Evans, Tatiana ForoudAbstract:ADO2 is an uncommon sclerosing bone disorder with incomplete penetrance and variable expressivity. Positional candidate studies were performed to identify the gene responsible for ADO2. In 11 of 12 kindreds, five different missense mutations were identified in the CLCN7 gene, indicating the genetic basis and possible dominant negative mechanism for ADO2. Introduction: Autosomal dominant osteopetrosis, type II (ADO2) is an uncommon sclerosing bone disorder with a distinct radiographic appearance and unique clinical characteristics. We present the results from our genetic studies designed to identify the ADO2 gene through a positional candidate approach. Methods: Having identified 12 families with ADO2, we initially performed linkage studies in our seven largest kindreds and observed a summed maximum LOD score of 15.91 at marker D16S521 on chromosome 16p13.3. Critical meiotic recombination events further narrowed the putative gene region to a 7.6-cM area, which contains the candidate genes ATP6L and chloride channel 7 (CLCN7). We screened affected individuals from each ADO2 family for mutations in these genes using direct sequencing. Identified mutations were subsequently confirmed through direct sequencing or restriction fragment length polymorphism analysis. We then calculated the overall disease penetrance rate after all available at-risk family members were assessed for CLCN7 gene mutations. Results: No ATP6L mutations were identified in affected subjects. Subsequently, as CLCN7 gene mutations were being reported, we identified two novel (L213F, R762L) and three known (G215R, R286W, R767W) missense mutations in 11 kindreds. In our large sample, disease penetrance was 66% (62 clinically affected individuals/94 subjects with the gene mutation). To date, nine different mutations have been discovered in the CLCN7 gene in 22 of 23 ADO2 families studied. Conclusions:We conclude that mutations in the CLCN7 gene are responsible for ADO2 and that genetic heterogeneity is unlikely to exist in this disorder. Based on the preponderance of missense mutations and the knowledge that chloride channels probably function as dimers, it seems that heterozygous CLCN7 gene mutations may cause ADO2 through a dominant negative mechanism.
Steven Mumm - One of the best experts on this subject based on the ideXlab platform.
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elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers schonberg disease chloride channel 7 deficiency osteopetrosis among the sclerosing bone disorders
Journal of Bone and Mineral Research, 2010Co-Authors: Lydia G Kempa, Steven Mumm, Michael P Whyte, William H. Mcalister, Fan Zhang, Deborah WenkertAbstract:Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schonberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency. © 2010 American Society for Bone and Mineral Research.
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elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers schonberg disease chloride channel 7 deficiency osteopetrosis among the sclerosing bone disorders
Journal of Bone and Mineral Research, 2010Co-Authors: Lydia G Kempa, Steven Mumm, Michael P Whyte, William H. Mcalister, Fan Zhang, Deborah WenkertAbstract:Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schonberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency.
Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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molecular pathology of renal chloride channels in dent s disease and bartter s syndrome
Experimental Nephrology, 2000Co-Authors: Rajesh V ThakkerAbstract:Recent advances in molecular biology have characterised a new class of chloride channels that are referred to as voltage-gated chloride channels (CLCs). To date 9 such CLCs (CLC-1 to CLC-7, CLC-Ka and CLC-Kb which are respectively encoded by the genes CLCN1 to CLCN7, CLCNKa and CLCNKb) have been identified in mammals. Mutations in 2 of these, referred to as CLC-5 and CLC-Kb, have been defined in the hypercalciuric nephrolithiasis disorders of Dent's disease and a form of Bartter's syndrome, respectively. In addition, other forms of Bartter's syndrome have been defined with mutations involving the bumetanide-sensitive sodium-potassium-chloride co-transporter (NKCC2) and the potassium channel ROMK. Finally, mutations of the thiazide-sensitive sodium chloride co-transporter (NCCT) are associated with Gitelman's syndrome, in which hypocalciuria and hypomagnesaemia are notable features. These molecular genetic studies have increased our understanding of the renal tubular mechanisms that regulate mineral homeostasis.
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clinical and genetic studies of clcn5 mutations in japanese families with dent s disease
Kidney International, 2000Co-Authors: Takashi Igarashi, Mitsunobu Shimadzu, Jun Inatomi, Toshio Ohara, Takashi Kuwahara, Rajesh V ThakkerAbstract:Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent's disease. Background Dent's disease is an X-linked renal tubular disorder that is characterized by low molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. The disease is caused by inactivation of a renal chloride channel gene, CLCN5 , that encodes a 746-amino acid protein with 12 to 13 transmembrane domains. The Japanese variant of Dent's disease has been observed to be less severe, and we have investigated two unrelated Japanese families for CLCN5 mutations. Methods Six patients from two unrelated families were studied. Leukocyte DNA from probands was used with CLCN5 -specific primers for polymerase chain reaction (PCR) amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products were determined to identify abnormalities in the gene. RNA extracted from the kidney, leukocytes, or urine sediments was used to characterize further the effects of the identified mutations. Results β 2 -microglobulinuria was detected in five patients, hypercalciuria in two patients, nephrolithiasis in three patients (2 of whom were females), and one 51-year-old man had renal failure. Two novel CLCN5 mutations consisting of an a to g transition at the invariant ag acceptor splice site of intron 5 and an intragenic deletion that encompassed the region between intron 3 and intron 6 were identified. The acceptor splice site mutation led to the utilization of two alternative cryptic splice sites in exon 6 that resulted in a frameshift or skipping of the exon 6. The deletional mutation, which resulted in a loss of exons 4, 5, and 6, is predicted to lead to a loss of domains 1 through 4. Both mutations predict truncated chloride channels that are likely to result in a functional loss. Conclusions The observations of renal failure in one male and nephrolithiasis in two females represent important new findings in this Japanese variant of Dent's disease that is associated with CLCN5 mutations. In addition, our study is the first to demonstrate the use of urinary sediment cells and renal tissue for the detection of CLCN5 transcript abnormalities. These results help to expand the spectrum of CLCN5 mutations associated with Dent's disease.
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idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in japanese children is due to mutations of the renal chloride channel clcn5
Journal of Clinical Investigation, 1997Co-Authors: Sarah E Lloyd, Thomas J. Jentsch, Willy Gunther, Simon H. S. Pearce, H. Kawaguchi, Takashi Igarashi, Rajesh V ThakkerAbstract:The annual urinary screening of Japanese children above 3 yr of age has identified a progressive proximal renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. The disorder, which has a familial predisposition and occurs predominantly in males, has similarities to three X-linked proximal renal tubular disorders that are due to mutations in the renal chloride channel gene, CLCN5. We have investigated four unrelated Japanese kindreds with this tubulopathy and have identified four different CLCN5 mutations (two nonsense, one missense, and one frameshift). These are predicted to lead to a loss of chloride channel function, and heterologous expression of the missense CLCN5 mutation in Xenopus oocytes demonstrated a 70% reduction in channel activity when compared with the wild-type. In addition, single-stranded conformation polymorphism (SSCP) analysis was found to be a sensitive and specific mutational screening method that detected > 75% of CLCN5 mutations. Thus, the results of our study expand the spectrum of clinical phenotypes associated with CLCN5 mutations to include this proximal renal tubular disorder of Japanese children. In addition, the mutational screening of CLCN5 by SSCP will help to supplement the clinical evaluation of the annual urinary screening program for this disorder.
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Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis.
Kidney international, 1997Co-Authors: Naoko Akuta, Sarah E Lloyd, Hiroshi Shiraga, Takeshi Matsuyama, Takashi Igarashi, Jeremy Cox, Seitarou Yokoro, Rajesh V ThakkerAbstract:Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. The annual urinary screening of Japanese children above three years of age has identified a progressive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. The disorder has been observed in over 60 patients and has a familial predisposition. Mutations of a renal chloride channel gene, CLCN5, have been reported in four such families, and we have undertaken studies in additional patients from 10 unrelated, non-consanguineous Japanese families to further characterize such CLCN5 mutations and to ascertain their prevalence. CLCN5 abnormalities were identified in 7 of the 10 unrelated patients and consisted of 5 mutations (2 nonsense, 1 frameshift and 2 missense), 1 deletion and 1 silent polymorphism. A clustering of these mutations in CLCN5 exons 8 and 10 was observed. Over 80% of the CLCN5 mutations could be readily detected by single stranded conformational polymorphism (SSCP) analysis, thereby providing a useful mutation screening method. Our results, which indicate that over 70% of Japanese patients with this renal tubulopathy have CLCN5 mutations, will help in the genetic and clinical evaluation of children at risk from this disorder.
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cloning and characterization of clcn5 the human kidney chloride channel gene implicated in dent disease an x linked hereditary nephrolithiasis
Genomics, 1995Co-Authors: Simon E. Fisher, I Van Bakel, Sarah E Lloyd, Simon H. S. Pearce, Rajesh V Thakker, Ian W CraigAbstract:Dent disease, an X-linked familial renal tubular disorder, is a form of Fanconi syndrome associated with proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, and eventual renal failure. We have previously used positional cloning to identify the 3' part of a novel kidney-specific gene (initially termed hClC-K2, but now referred to as CLCN5), which is deleted in patients from one pedigree segregating Dent disease. Mutations that disrupt this gene have been identified in other patients with this disorder. Here we describe the isolation and characterization of the complete open reading frame of the human CLCN5 gene, which is predicted to encode a protein of 746 amino acids, with significant homology to all known members of the ClC family of voltage-gated chloride channels. CLCN5 belongs to a distinct branch of this family, which also includes the recently identified genes CLCN3 and CLCN4. We have shown that the coding region of CLCN5 is organized into 12 exons, spanning 25-30 kb of genomic DNA, and have determined the sequence of each exon-intron boundary. The elucidation of the coding sequence and exon-intron organization of CLCN5 will both expedite the evaluation of structure/function relationships of these ion channels and facilitate the screening of other patients with renal tubular dysfunction for mutations at this locus.