A gene from the Xp22.3 region shares homology with voltage-gated chloride channels

Slegtenhorst, Marjon A. van; T.Bassl, Maria; Borsanil, Gluseppe; Wapenaar, Martin C.; Ferrero, Giovanni Battista; Concillls, Lisa de; Rugarli, Elena I.; Grillo, A.; Bazzoli, Franco; Y.Zoghbl, Huda; Ballabio, Andrea

doi:10.1093/hmg/3.4.547

Cited by 99 publications

(53 citation statements)

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“…However, C1C-6 belongs to a distant branch of this family and its closest known cousin is on chromosome 16. The other C1C genes are located on different human chromosomes: C1C-1 on 7p35 [14], C1C-2 on 3q26-3qter [31], C1C-3 on chromsome 4 [18], C1C-4 on Xp22.3 [10] and C1C-5 on Xpl 1.22 [11].…”

Section: Discussionmentioning

confidence: 99%

“…In a single mammalian species, seven different C1C genes have been described so far [5][6][7][8][9][10][11][12]. These display differential tissue distribution and perform diverse functions.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in this chloride channel lead to X-linked kidney stone disease [11,17]. The function of other members of this gene family (CIC-Ka and CIC-Kb [7,8], C1C-3 [9,18] and C1C-4 [2,10]), however, is currently obscure. This problem is compounded by the fact that functional expression as chloride channels, as reported by one group [7,9], could not be reproduced by other groups [2,8,18].…”

Section: Introductionmentioning

confidence: 99%

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ClC‐6 and ClC‐7 are two novel broadly expressed members of the CLC chloride channel family

1995

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We cloned two novel members of the CLC chloride channel family from rat and human brain. CIC-6 is a 97-kDa protein, and CIC-7 a 89-kDa protein roughly 45% identical with CIC-6. Together they define a new branch of this gene family. Both genes are very broadly expressed, e.g. in brain, testes, muscle and kidney. In mouse embryos, both genes are expressed as early as day 7. While the human gene for CIC-6 is located on human chromosome lp36 and shares this region with hCIC-Ka and hCIC-Kb, CIC-7 is on 16p13. CIC-6 has a highly conserved glycosylation site between transmembrane domains D8 and D9, while CIC-7 is the only known eukaryotic CIC protein which lacks this site. Hydropathy analysis indicates that domain D4 cannot serve as a transmembrane domain. Both CIC-6 and CIC-7 cannot be expressed as chloride channels in Xenopus oocytes, either singly or in combination.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ClC‐6 and ClC‐7 are two novel broadly expressed members of the CLC chloride channel family

1995

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“…Little is known about the functions of the CLCN4 protein, a chloride channel that mediates voltage-dependent electrogenic Cl À /H + exchange (Jentsch 2008). In human, CLCN4 is expressed in multiple tissues, especially in excitable tissues, such as heart, brain, and skeletal muscle (van Slegtenhorst et al 1994).…”

Section: Genome Research 405mentioning

confidence: 99%

Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X

et al. 2011

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In Mus spretus, the chloride channel 4 gene Clcn4-2 is X-linked and dosage compensated by X up-regulation and X inactivation, while in the closely related mouse species Mus musculus, Clcn4-2 has been translocated to chromosome 7. We sequenced Clcn4-2 in M. spretus and identified the breakpoints of the evolutionary translocation in the Mus lineage. Genetic and epigenetic differences were observed between the 59ends of the autosomal and X-linked loci. Remarkably, Clcn4-2 introns have been truncated on chromosome 7 in M. musculus as compared with the X-linked loci from seven other eutherian mammals. Intron sequences specifically preserved in the X-linked loci were significantly enriched in AT-rich oligomers. Genome-wide analyses showed an overall enrichment in AT motifs unique to the eutherian X (except for genes that escape X inactivation), suggesting a role for these motifs in regulation of the X chromosome.[Supplemental material is available for this article. The sequencing data from this study have been submitted to GenBank (http://www.ncbi.nlm.nih.gov/Genbank/) under accession nos. HM053970 and HM053971.] In mammals, X-linked genes are regulated by special epigenetic mechanisms, because females have two X chromosomes and males only have one, while autosomes are present in two copies. These regulatory mechanisms are (1) X up-regulation in both sexes to balance expression between X-linked and autosomal genes (Gupta et al. 2006;Nguyen and Disteche 2006) and (2) X inactivation in females (Lyon 1961). Ohno (1967) predicted that due to these unique regulatory mechanisms the gene content of the X chromosome would be highly conserved between mammalian species. The chloride channel 4 gene (hereafter called Clcn4 when considering multiple mammalian species) illustrates a rare exception to this conservation, since it is X-linked in most mammals including human, primates, dog, cow, and horse (CLCN4), as well as rat (Clcn4-2), but located on chromosome 7 in the laboratory mouse (Clcn4-2) (derived from a mixture of M. musculus musculus and M. musculus domesticus and thereafter referred to as M. musculus) (Palmer et al. 1995;Rugarli et al. 1995;Flicek et al. 2010).Clcn4-2 is X-linked in the wild-derived mouse M. spretus, suggesting that it was translocated to an autosome in one branch of Mus (musculus) during evolution (Palmer et al. 1995;Rugarli et al. 1995). We have previously used F1 mice from crosses between Mus species to show that Clcn4-2 is subject to X inactivation (Rugarli et al. 1995) and that its expression is doubled on the active X from M. spretus compared with each autosomal allele from M. musculus (Adler et al. 1997). Thus, Clcn4-2 is subject to both types of dosage-compensation mechanisms, X up-regulation, and X inactivation. The different location of this gene in closely related mouse species provides a system to explore whether X-linked genes differ from autosomal genes in terms of DNA sequence and epigenetic modifications. Our hypothesis based on studies in other organisms is that specific sequence moti...

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“…Another gene cluster, consisting of the genes for ocular albinism type 1 (OA1) , the apical protein Xenopus laevis-like (APXL) , and a voltage gated chloride channel (CLCN4) (van Slegtenhorst et al 1994), is located between STS and AMELX. Although closely linked in humans, these genes are well separated in mice (Fig.…”

Section: Human X Chromosome Genes With Altered Murine Homolog X Chrommentioning

confidence: 99%

Man to Mouse—Lessons Learned from the Distal End of the Human X Chromosome

Blaschke¹,

Rappold²

1997

Genome Res.

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A gene from the Xp22.3 region shares homology with voltage-gated chloride channels

Cited by 99 publications

References 0 publications

ClC‐6 and ClC‐7 are two novel broadly expressed members of the CLC chloride channel family

ClC‐6 and ClC‐7 are two novel broadly expressed members of the CLC chloride channel family

Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X

Man to Mouse—Lessons Learned from the Distal End of the Human X Chromosome

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