Disease relevance of SLC12A6

• Inactivating mutations in three members of the SLC12 gene family result in Mendelian disease; Bartter syndrome type I in the case of SLC12A1, Gitelman syndrome for SLC12A3, and peripheral neuropathy in the case of SLC12A6 [1].
• Recessive mutations of the potassium chloride co-transporter 3 gene ( SLC12A6 , KCC3 ) cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN) [2].
• IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness [3].
• Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN) is a devastating neurodegenerative disorder that is transmitted as an autosomal recessive trait [4].

Psychiatry related information on SLC12A6

• Our data strongly suggest that rare variants of SLC12A6 may represent risk factors for bipolar disorder [2].
• Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum [5].

High impact information on SLC12A6

• ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q [5].
• The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum [5].
• The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional [5].
• KCC3 was expressed in many, but not all cells of the inner ear K(+) recycling pathway [6].
• These data indicate that KCC3 is an important KCC isoform that may be involved in cell proliferation [7].

Biological context of SLC12A6

• The human KCC3 and KCC4 genes are located on chromosomes 5p15 and 15q14, respectively [8].
• The KCl cotransporter isoform KCC3 can play an important role in cell growth regulation [7].
• KCC3 activity is sensitive to [(dihydroindenyl)oxy] alkanoic acid (DIOA) and N-ethylmaleimide and is regulated by tyrosine phosphorylation [7].
• Hydrophobicity analysis of the KCC3 amino acid sequence showed an almost identical pattern to KCC1, suggesting 12 membrane-spanning segments, a large extracellular loop with potential N-glycosylation sites, and cytoplasmic N- and C-terminal regions [9].
• Finally, both KCC3 and KCC4 are crucial for proximal tubular cell volume regulation [10].

Anatomical context of SLC12A6

• The expression of mouse KCC3 in Xenopus laevis oocytes reveals the expected functional characteristics of a K+Cl- cotransporter: Cl--dependent uptake of 86Rb+ which is strongly activated by cell swelling and weakly sensitive to furosemide [8].
• KCC3 is predominantly expressed in kidney, heart, and brain, and is also expressed in skeletal muscle, placenta, lung, liver, and pancreas [11].
• KCC3, initially cloned from vascular endothelial cells, is widely but not universally distributed and has an unknown physiological significance [7].
• Here we show a tight link between the expression and activity of KCC3 and cell growth by a NIH/3T3 fibroblast expression system [7].
• The KCC3 mRNA was highly expressed in brain, heart, skeletal muscle, and kidney, showing a distinct pattern and size from KCC1 and KCC2 [9].

Associations of SLC12A6 with chemical compounds

• KCC3 transiently expressed in human embryonic kidney (HEK)-293 cells fulfilled three criteria for increased expression of K-Cl cotransport: stimulation of cotransport by swelling, treatment with N-ethylmaleimide, or treatment with staurosporine [11].
• Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy [12].
• Stable overexpression of KCC3 cDNA in HEK293 cells produced a glycoprotein of approximately 150 kDa, which was reduced to 120 kDa by glycosidase digestion [9].
• NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter [13].
• One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity [12].

Other interactions of SLC12A6

• Although widely expressed, KCC3 transcripts are the most abundant in heart and kidney, and KCC4 is expressed in muscle, brain, lung, heart, and kidney [8].
• KCC3 shares 75-76% identity at the amino acid level with human, pig, rat, and rabbit KCC1 and 67% identity with rat KCC2 [11].
• The KCC3 mRNA level in endothelial cells increased on treatment with VEGF and decreased with the proinflammatory cytokine tumor necrosis factor alpha, whereas KCC1 mRNA levels remained unchanged [9].
• A few reports indicate that the NO/cGMP/PKG signaling pathway regulates KCC1 and KCC3 mRNA expression in VSMCs at the post-transcriptional level [14].
• Through the use of haplotype analysis we have confirmed the presence of a founder haplotype in the FC population, and identified critical recombinants which reduce the ACCPN candidate interval to a approximately 2 cM or 1000 Kb region flanked by markers D15S1040 and ACTC [15].

Analytical, diagnostic and therapeutic context of SLC12A6

• Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter [11].
• The KCC3 genomic localization was shown to be 15q13 by fluorescence in situ hybridization [9].
• Radiation hybrid analysis placed KCC3 within an area associated with juvenile myoclonic epilepsy [9].
• Immunofluorescence reveals basolateral expression of KCC3 protein along the entire length of the proximal tubule, in both the mouse and rat [13].
• Using isoform-specific primers, mRNA transcripts of KCC1, KCC3 and KCC4 were identified by reverse transcriptase polymerase chain reaction (RT-PCR) in several types of cervical cell, and confirmed by digestion with specific restriction endonucleases [16].

References