Novel truncating and missense mutations of the
            <i>KCC3</i>
            gene associated with Andermann syndrome

Uyanık, G.; Elçioğlu, Nursel; Penzien, Johannes M.; Groß, Claudia; Yılmaz, Yasin; Ölmez, Akgün; Demir, Ercan; Wahl, Dagmar; Scheglmann, K.; Winner, Beate; Bogdahn, Ulrich; Topaloǧlu, Haluk; Hehr, Ute; Winkler, Juergen

doi:10.1212/01.wnl.0000204181.31175.8b

Cited by 58 publications

(60 citation statements)

References 16 publications

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“…We have recently demonstrated that this loss of function includes the failure of the transporter to interact with braintype creatine kinase (CK-B) (6). However, the R207C missense mutation is predicted to result in a full-length protein bearing an amino acid exchange that should not impact the interaction of KCC3 with CK-B, which suggests that other mechanisms may be involved in KCC3 dysfunction in HMSN/ACC (5).…”

Section: Rbmentioning

confidence: 99%

“…Ten HMSN/ACC-causing KCC3 mutations have been reported, which include six randomly distributed frameshift mutations, two carboxyl terminus-truncating nonsense mutations, and two missense mutations (2,4,5); thus, the most frequent alterations in HMSN/ACC are the total or partial elimination of KCC3 carboxyl-terminal regions. Data collected from heterologous expression studies in Xenopus oocytes using truncated KCC3 mutants revealed that the loss of the last 140 amino acids is sufficient to abolish the KCC3-driven flux of 86 …”

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confidence: 99%

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Transit Defect of Potassium-Chloride Co-transporter 3 Is a Major Pathogenic Mechanism in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Salin-Cantegrel

Rivière

Shekarabi

et al. 2011

Journal of Biological Chemistry

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Missense and protein-truncating mutations of the human potassium-chloride co-transporter 3 gene (KCC3) cause hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), which is a severe neurodegenerative disease characterized by axonal dysfunction and neurodevelopmental defects. We previously reported that KCC3-truncating mutations disrupt brain-type creatine kinase-dependent activation of the co-transporter through the loss of its last 140 amino acids. Here, we report a novel and more distal HMSN/ACCtruncating mutation (3402C3 T; R1134X) that eliminates only the last 17 residues of the protein. This small truncation disrupts the interaction with brain-type creatine kinase in mammalian cells but also affects plasma membrane localization of the mutant transporter. Although it is not truncated, the previously reported HMSN/ACC-causing 619C3 T (R207C) missense mutation also leads to KCC3 loss of function in Xenopus oocyte flux assay. Immunodetection in Xenopus oocytes and in mammalian cultured cells revealed a decreased amount of R207C at the plasma membrane, with significant retention of the mutant proteins in the endoplasmic reticulum. In mammalian cells, curcumin partially corrected these mutant protein mislocalizations, with more protein reaching the plasma membrane. These findings suggest that mis-trafficking of mutant protein is an important pathophysiological feature of HMSN/ACC causative KCC3 mutations.

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Section: Rbmentioning

confidence: 99%

mentioning

confidence: 99%

Transit Defect of Potassium-Chloride Co-transporter 3 Is a Major Pathogenic Mechanism in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Salin-Cantegrel

Rivière

Shekarabi

et al. 2011

Journal of Biological Chemistry

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“…The gene SLC12A6 is located on chromosome 15q13-14 (Hiki et al, 1999;Mount et al, 1999;Race et al, 1999). Several groups have demonstrated that mutations in SLC12A6 are causative for the recessively inherited Andermann syndrome (ACCPN, OMIM %218000), a severe neurological disorder characterized by agenesis of the corpus callosum, peripheral neuropathy (Howard et al, 2002bUyanik et al, 2006) and psychoses (Filteau et al, 1991). The chromosomal region 15q13-14 represents a shared susceptibility locus for a variety of neuropsychiatric disorders including periodic catatonia, bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder (Elmslie, 1997a, b;Elmslie et al, 1997;Sander et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…These cotransporters have recently gained attention in the field of neuroscience, as they facilitate neuronal response to gamma-aminobutyric acid and glycine (Mercado et al, 2004). Furthermore, several members of the cation-chloride co-transporter family are involved in hereditary diseases, such as Gitelman's, Bartter's, Gordon's and Andermann's syndromes, and have shown associations with bipolar disorder (Bianchetti et al, 1992;Dupre et al, 2003;Filteau et al, 1991;Gamba, 2005;Gitelman et al, 1966;Gordon, 1986;Howard et al, 2002bHoward et al, , 2003Meyer et al, 2005;Uyanik et al, 2006). The crucial role of cation co-transporters for neuronal development is also supported by animal studies in which knockout mice for cation-chloride co-transporters display a plethora of symptoms such as deafness, locomotor deficits, severe central and peripheral neurodegeneration, and sensorimotor gating defects (Boettger et al, 2002(Boettger et al, , 2003Hubner et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

Moser

Ekawardhani

Kumsta

et al. 2008

Neuropsychopharmacol

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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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“…6 Additional KCC3 mutations were also found in HMSN/ACC patients. 4,7,8 KCC3 belongs to a small family of electroneutral cotransporters and has been implicated in cell volume control by extrusion of potassium and chloride ions along with water to the extracellular environment. 9 The observation of a watery swelling of axons and of spheroids has been established using histochemical methods.…”

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confidence: 99%

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system

et al. 2016

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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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Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome

Abstract: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

Cited by 58 publications

References 16 publications

Transit Defect of Potassium-Chloride Co-transporter 3 Is a Major Pathogenic Mechanism in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Transit Defect of Potassium-Chloride Co-transporter 3 Is a Major Pathogenic Mechanism in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system

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