Wilson et al. (1990) isolated and sequenced a 2.3-kb cDNA clone coding for the entire sequence of human IDS from an endothelial cell cDNA library. Analysis of the deduced 550-amino acid precursor indicated that IDS has a 25-amino acid amino-terminal signal sequence, followed by 8 amino acids that are removed from the proprotein. An internal proteolytic cleavage occurs to produce the mature 42- and 14-kD polypeptides observed in liver, kidney, lung, and placenta. A strong sequence homology was found with human arylsulfatases A, B, and C, and human glucosamine-6-sulfatase. Northern blot analysis detected 3 major RNA species (5.7, 5.4, and 2.1 kb) and 1 minor species (1.4 kb). Although the arg468-to-trp mutation ( 300823.0012) was associated with a mild form of MPS II, Whitley et al. (1993) found very severe MPS II ( 309900) manifestations in a boy who was found to have a mutation in the same codon: a G-to-A transition at nucleotide 1403 of the IDS gene resulted in substitution of glutamine for arginine-468 (R468Q). In a note added in proof, it was reported that fibroblast cultures showed a large acrocentric supernumerary marker chromosome, which presumably was responsible for the quantitatively and qualitatively atypical features of the proband's face. The proband died at the age of 23 months.

Deletion of the Hunter gene and both DXS466 and DXS304 in a patient with mucopolysaccharidosis type II. Mutation analysis of the iduronate-2-sulfatase gene in patients with mucopolysaccharidosis type II (Hunter syndrome). Choi et al. (2011) identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5 present in 8 of 22 human aldosterone-producing adrenal adenomas: G151R (600734.0004) and L168R. In addition, Choi et al. (2011) identified heterozygosity for a missense mutation in KCNJ5 (T158A; 600734.0002) in a family segregating autosomal dominant hyperaldosteronism type III (HALD3; 613677). This mutation caused increased sodium conductance and severe aldosteronism and massive bilateral adrenal hyperplasia.

In a large 4-generation Chinese family with autosomal dominant long QT syndrome mapping to chromosome 11q23.3-q23.4 (LQT13; 613485), Yang et al. (2010) sequenced the candidate gene KCNJ5 and identified heterozygosity for a missense mutation (G387R; 600734.0001) in affected individuals. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies demonstrated that the mutation has a dominant-negative effect that results in near-complete loss of channel activity compared to wildtype. In a father and 2 daughters with hyperaldosteronism type III (HALD3; 613677), Choi et al. (2011) identified heterozygosity for an A-to-G transition in the KCNJ5 gene resulting in a threonine-to-alanine substitution at codon 158 (T158A). This mutation was present in affected family members and was not identified in 900 control alleles. All 3 patients had massive adrenal hyperplasia and required bilateral adrenalectomy in childhood. Threonine-158 is conserved among KCNJ5 orthologs and other inward rectifiers and lies in the loop between the selectivity filter and the second transmembrane domain. The T158A mutation eliminates hydrogen bonds that constrain the structure of the KCNJ5 potassium channel. the total liability of VWR for any loss or damage suffered by a customer in connection with the supply of the products under this contract is limited to the invoice price of the products in relation to which loss or damage is claimed. Authorisation to return products damaged during delivery must be requested within 3 days of delivery. VWR has the right to repair and return damaged products. Palmieri et al. (1992) isolated a 1.2-Mb YAC contig spanning the IDS gene. Several putative CpG islands were identified in the region, suggesting the presence of other genes. Southern analysis of DNA from 25 unrelated Italian MPS II patients uncovered 4 with deletions or rearrangements in the IDS gene. DNA from a patient with a translocation breakpoint in the gene permitted orientation of the contig in relation to the centromere.

Caveat to genotype-phenotype correlation in mucopolysaccharidosis type II: discordant clinical severity of R468W and R468Q mutations of the iduronate-2-sulfatase gene. In the family with hyperaldosteronism reported by Geller et al. (2008), Choi et al. (2011) identified a missense mutation in the potassium channel gene KCNJ5 at codon 158 (T158A; 600734.0002). This mutation produced increased sodium conductance and caused severe hypertension. Choi et al. (2011) also identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5, G151R (600734.0004), and L168R, that were present in 8 of 22 human aldosterone-producing adrenal adenomas studied. These 2 mutations produced increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. The customer is required to ensure that the use of any products supplied by VWR does not infringe the intellectual property rights of any third party and the customer shall indemnify VWR against any claims made against VWR by any third party in relation to any such infringement or alleged infringement. Customers who exceed their credit limits will be asked to pay in advance for additional products and/or services until the account is settled.

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After exclusion of chimeric fusion of CYP11B1/CYP11B2 or mutation in the AT1R gene ( 106165) in a mother and daughter with severe aldosteronism requiring total adrenalectomy, Charmandari et al. (2012) sequenced the candidate genes KCNK3 ( 603220), KCNK5 ( 603493), KCNK9 ( 605874), and KCNJ5, and identified heterozygosity for a missense mutation in the KCNJ5 gene (I157S; 600734.0006).

Whitley, C. B., Anderson, R. A., Aronovich, E. L., Crotty, P. L., Anyane-Yeboa, K., Russo, D., Warburton, D. GIRK4 confers appropriate processing and cell surface localization to G-protein-gated potassium channels.

Fujimi | No. 60073 | 1:350

In 2 of 22 aldosterone-producing adrenal adenomas (APAs) from unrelated patients with primary hyperaldosteronism ( 613677), Choi et al. (2011) identified a somatic G-to-A transition at position chr11:126,286,829 in the KCNJ5 gene, resulting in a gly151-to-arg (G151R) substitution. Expression studies of two novel in cis-mutations identified in an intermediate case of Hunter syndrome. Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers. Bondeson, M.-L., Dahl, N., Malmgren, H., Kleijer, W. J., Tonnesen, T., Carlberg, B.-M., Pettersson, U. Mulatero, P., Tauber, P., Zennaro, M.-C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., and 10 others.

The G-protein-gated atrial K+ channel I-KACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. In affected members of a large 4-generation Chinese family with autosomal dominant long QT syndrome (LQT13; 613485), Yang et al. (2010) identified heterozygosity for a 1473C-G transversion in the KCNJ5 gene, resulting in a gly387-to-arg (G387R) substitution at a highly conserved residue. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies in HEK293 cells cotransfected with Kir3.4 and Kir3.1 (KCNJ3; 601534) demonstrated that the mutant has a dominant-negative effect resulting in drastic reduction of inward currents compared to wildtype. In addition, plasma membrane and intracellular expression levels of Kir3.4 and Kir3.1 were markedly reduced in HEK293 cells cotransfected with the mutation compared to wildtype. In a 12-year-old boy with MPS II, Sukegawa et al. (1992) identified a missense mutation in the IDS gene (300823.0001). Wilson et al. (1991) found a deletion or gene rearrangement in 7 of 23 patients with mucopolysaccharidosis type II (Hunter syndrome; 309900) of Australian and British origin. In 2 of 14 unrelated German MPS II patients, structural alteration of the IDS gene was found by Southern analysis using an IDS cDNA clone as a probe. In one of these patients, a severely affected male, no Southern fragments were detected. Mucopolysaccharidosis type II (Hunter syndrome): mutation 'hot spots' in the iduronate-2-sulfatase gene.In an Italian mother and daughter with primary aldosteronism, Mulatero et al. (2012) identified heterozygosity for a missense mutation in the KCNJ5 gene (G151E; 600734.0005). Tomatsu, S., Orii, K. O., Bi, Y., Gutierrez, M. A., Nishioka, T., Yamaguchi, S., Kondo, N., Orii, T., Noguchi, A., Sly, W. S.