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

Coto, Eliécer; Rodrı́guez, Julián; Jeck, Nikola; Álvarez, Victoria; Stone, Rosário; Loris, C; Rodríguez, Luis M.; Fischbach, Michel; Seyberth, Hannsjörg W.; Santos, Fernando

doi:10.1111/j.1523-1755.2004.00388.x

Cited by 61 publications

(30 citation statements)

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“…They were mainly found in heterozygous compound subjects, except for c.1180 ϩ 1GϾT, which is highly prevalent in the Gypsy population. 17 In the entire set of 172 point mutations, 100 have not been described before (53 missense, 19 frameshift, 16 splice, 6 nonsense, and 6 in-frame mutations; Supplementary Table 1, A-C). Supplementary Table 2 sums up the novel missense mutations and their in silico predictions.…”

Section: Results Of the First Screen By Direct Sequencing Analysismentioning

confidence: 99%

Spectrum of Mutations in Gitelman Syndrome

Vargas‐Poussou

Dahan

Kahila

et al. 2011

Journal of the American Society of Nephrology

200

194

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Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligationdependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.

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Section: Results Of the First Screen By Direct Sequencing Analysismentioning

confidence: 99%

Spectrum of Mutations in Gitelman Syndrome

Vargas‐Poussou

Dahan

Kahila

et al. 2011

Journal of the American Society of Nephrology

200

194

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“…Finally, in 7% of patients, three or more mutations occur. Only one study, in 20 patients from 12 different European families who were of Gypsy origin, revealed the same mutation in all patients (64). All these patients were homozygous for a substitution of G for T in the first position of intron 9, affecting consensus donor splice site motif and resulting in a nonsense protein.…”

Section: A Gitelman's Diseasementioning

confidence: 99%

“…ac.uk/uwcm/mg/hgmd0.html). There are ϳ100 different mutations spread throughout the SLC12A3 gene, from the amino-to the carboxy-terminal domain of TSC, without preference for a particular location along the protein (55, 64,67,241,245,259,264,271,281,307,339,377,395,396,398,442,449). Figure 21 illustrates the proposed TSC secondary structure and location of the majority of reported mutations.…”

Section: A Gitelman's Diseasementioning

confidence: 99%

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

Gamba

2005

Physiological Reviews

697

754

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Electroneutral cation-Cl−cotransporters compose a family of solute carriers in which cation (Na+or K+) movement through the plasma membrane is always accompanied by Cl−in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na+−Cl−cotransporter, two genes encoding loop diuretic-sensitive Na+−K+−2Cl−cotransporters, and four genes encoding K+−Cl−cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl−concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.

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“…Growth impairment is frequently described in Bartter's syndrome (22). Gitelman's syndrome, traditionally considered as asymptomatic or responsible for mild clinical manifestations (9), has been reported to be accompanied by short stature in over 30% of children (8).…”

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confidence: 99%

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

Gil‐Peña¹,

García-López²,

Álvarez-García³

et al. 2009

American Journal of Physiology-Renal Physiology

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of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment. Am J Physiol Renal Physiol 297: F639-F645, 2009. First published July 8, 2009 doi:10.1152/ajprenal.00188.2009.-Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped (n ϭ 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (ϮSD) being 67. . GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.tubulopathies; chondrocyte; cartilage GROWTH RETARDATION IS FREQUENTLY found in primary hypokalemic tubular disorders (32). Potential pathogenic factors of growth impairment in these tubulopathies include maintained metabolic acidosis, polyuria with decreased food intake and repeated dehydration episodes, disturbed bone mineralization, sodium deficit, and potassium depletion. In children with renal tubular acidosis, growth retardation is common and is ameliorated or reversed after sustained correction of metabolic acidosis (29). Metabolic acidosis disturbs normal growth through various mechanisms such as the stimulation of protein catabolism (18), interference with growth hormone (GH) action (21), and the alteration of the structure and dynamics of growth cartilage (5). In hypokalemic tubulopathies associated with alkalosis, Bartter's or Gitelman's syndromes, the adverse effect on growth is not well documented and the response of growth to treatment is rather unpredictable. Growth impairment is frequently described in Bartter's syndrome (22). Gitelman's syndrome, traditionally considered as asymptomatic or responsible for mild clinical manifestations (9), has been reported to be accompanied by short stature in over 30% of children (8).Although clinical cases of isolated GH deficiency as well as improvement of growth rate following administration of indomethacin have been reported in patients with Gitelman's syndrome, the...

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

Cited by 61 publications

References 19 publications

Spectrum of Mutations in Gitelman Syndrome

Spectrum of Mutations in Gitelman Syndrome

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

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