Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031117 (peripheral neuropathy)
 10,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN) is a devastating neurodegenerative disorder that is transmitted as an autosomal recessive trait. Genealogical studies in a large number of affected French Canadian individuals suggest that ACCPN results from a single founder mutation. A genomewide search using 120 microsatellite DNA markers in 14 French Canadian families allowed the mapping of the ACCPN gene to a 5-cM region on chromosome 15q13-q15 that is flanked by markers D15S1040 and D15S118. A maximum two-point LOD score of 11.1 was obtained with the marker D15S971 at a recombination fraction of 0. Haplotype analysis and linkage disequilibrium support a founder effect. These findings are the first step in the identification of the gene responsible for ACCPN, which may shed some light on the numerous conditions associated with the progressive peripheral neuropathy or agenesis of the corpus callosum.
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PMID:The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. 855 70

Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN [MIM 2180000]) is an autosomal recessive disease characterised by progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. The ACCPN gene was mapped in 1996 to a 4 cM region on chromosome 15. We have since collected additional French Canadian (FC) families and typed a total of 11 polymorphic markers spanning approximately 18 cM on chromosome 15. 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. Linkage disequilibrium analysis supports the haplotype data, and suggests that the ACCPN gene lies nearest to marker D15S1232.
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PMID:Fine mapping the candidate region for peripheral neuropathy with or without agenesis of the corpus callosum in the French Canadian population. 1210 14

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. 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. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non-French Canadian families. 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. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system.
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PMID:The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. 1236 12

Several members of the cation-chloride cotransporter (solute carrier family 12, SLC12) gene family are expressed within the central nervous system, with one family member, the K+-Cl- cotransporter KCC2, exclusive to neurons. These transporters are best known for their roles in cell volume regulation and epithelial salt transport, but are increasingly receiving attention in neuroscience. In particular, intracellular chloride activity and hence the neuronal response to GABA and glycine appears to be determined by a balance between chloride efflux and influx through KCC2 and the Na+-K+-2Cl- cotransporter NKCC1, respectively. This relationship has important implications for neuronal development, sensory perception, neuronal excitability, and the response to neuronal injury. Finally, the association between loss of function in the K+-Cl- cotransporter KCC3, with a severe peripheral neuropathy associated with agenesis of the corpus callosum, has revealed an unexpected role for K+-Cl- cotransport in the development and/or maintenance of both the central and peripheral nervous systems.
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PMID:Electroneutral cation-chloride cotransporters in the central nervous system. 1499 62

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). SLC12A6 is localized on chromosome 15q14, a region where linkage to schizophrenia and bipolar disorder has previously been shown. Mutation analysis of SLC12A6 was carried out by direct sequencing of PCR-generated DNA fragments in two affected members of a multiplex family, and three non-affected individuals. A case-control study was performed to assess association of variants with bipolar disorder and schizophrenia in a large sample. Several variants including two rare single nucleotide polymorphisms (G/A, G/A) in the promoter and 5'-UTR, and a thymidine insertion in intron 4 were found. The two G variants and the insertion variant were co-inherited with chromosome 15-related schizophrenia in a large family that strongly supports the region on chromosome 15q14-15 between markers D15S144 and D15S132. Furthermore, they are in linkage disequilibrium with each other, and significantly associated with bipolar disorder in a case-control study. Our data strongly suggest that rare variants of SLC12A6 may represent risk factors for bipolar disorder.
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PMID:Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder. 1609 36

We have previously reported CNS and locomotor deficits in KCC3 knockout mice, an animal model of agenesis of the corpus callosum associated with peripheral neuropathy (ACCPN) [Howard, H.C., Mount, D.B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.B., Prevost, C., Horst, J., Simonati, A., Lemcke, B., Welch, R., England, R., Zhan, F.Q., Mercado, A., Siesser, W.B., George, A.L., Jr., McDonald, M.P., Bouchard, J.P., Mathieu, J., Delpire, E., Rouleau, G.A., 2002. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat. Genet. 32, 384-392]. To assess the role of KCC3 in peripheral axon and/or myelin development and maintenance, we determined its expression and performed a detailed morphometric analysis of sciatic nerves. Sciatic nerves of juvenile wild-type mice, but not of adult, express KCC3. In the knockout, Schwann cell/myelin development appears normal at P3, but axons are swollen. At P8 and into P30, some fibers accumulate fluid periaxonally. These initial swelling pathologies are followed by axon and myelin degeneration in adult nerves, leading to reduction in nerve conduction velocity. Mutant mice also exhibit decreased sensitivity to noxious pain. This evidence for fluid-related axonopathy, which ultimately result in neurodegeneration, implicates cell volume regulation as a critical component of peripheral nerve maintenance.
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PMID:Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout mice. 1765 77

The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane. The gene (SLC12A6) is located on chromosome 15q14, a region that has previously shown linkage with bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder. Furthermore, recessively inherited mutations of SLC12A6 cause Andermann syndrome, characterized by agenesis of the corpus callosum, which is associated with peripheral neuropathy and psychoses. Recently, we have demonstrated the association of two G/A promoter polymorphisms of SLC12A6 with bipolar disorder in a case-control study, and familial segregation of the rare variants as well as a trend toward association with schizophrenia. To investigate functional consequences of these polymorphisms, lymphocyte DNA was extracted, bisulfite modified, and subsequently sequenced. To investigate SLC12A6 promoter activity, various promoter constructs were generated and analyzed by luciferase reporter gene assays. We provide evidence that the G- allele showed a significant reduction of reporter gene expression. In human lymphocytes, the allele harboring the rare upstream G nucleotide was found to be methylated at the adjacent C position, possibly accountable for tissue-specific reduction in gene expression in vivo. Here we demonstrate functionality of an SNP associated with psychiatric disease and our results may represent a functional link between genetic variation and an epigenetic modification.
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PMID:Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site. 1853 2

Nerve conduction requires the fine tuning of ionic currents through delicate interactions between axons and Schwann cells. The K(+)-Cl(-) cotransporter (KCC) family includes four isoforms (KCC1-4) that play an important role in the maintenance of cellular osmotic homeostasis via the coupled electroneutral movement of K(+) and Cl(-) with concurrent water flux. Mutation in SLC12A6 gene encoding KCC3 results in an autosomal recessive disease, known as agenesis of the corpus callosum associated with peripheral neuropathy. Nevertheless, the role of KCC3 in nerve function remains a puzzle. In this study, the microscopic examination of KCC isoforms expressed in peripheral nerves showed high expression of KCC2-4 in nodal segments of the axons and in the perinucleus and microvilli of Schwann cells. The KCC inhibitor [[(dihydroindenyl)oxy]alkanoic acid] but not the Na(+)-K(+)-2Cl(-)-cotransport inhibitor (bumetanide) dose-dependently suppressed the amplitude and area of compound muscle action potential, indicating the involvement of KCC activity in peripheral nerve conduction. Furthermore, the amplitude and area under the curve were smaller, and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than in nerves from wild-type mice, while the expression pattern of KCC2 and KCC4 was similar in KCC3 kockout and wild-type strains. KCC3(-/-) mice also manifested a prominent motor deficit in the beam-walking test. This is the first study to demonstrate that the K(+)-Cl(-) cotransporter activity of KCC3 contributes to the propagation of action potentials along peripheral nerves.
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PMID:Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves. 2054 48

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.
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PMID:KCC3 axonopathy: neuropathological features in the central and peripheral nervous system. 2723 Apr 13

Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T(991) tonically inhibits KCC3; however, cell swelling triggers Thr(991) dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr(991) phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3(T991A/T991A) mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase-regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration.
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PMID:Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. 2748 15


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