KCNE1-like Gene Is Deleted in AMME Contiguous Gene Syndrome: Identification and Characterization of the Human and Mouse Homologs

Piccini, Monica; Vitelli, Francesca; Seri, Marco; Galietta, Luis J. V.; Morán, Óscar; Bulfone, Alessandro; Banfi, Sandro; Pober, Barbara R.; Renieri, Alessandra

doi:10.1006/geno.1999.5904

Cited by 67 publications

(56 citation statements)

References 12 publications

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“…39 However, KCNE5 also seems a promising gene because of its restricted pattern of expression in CNS, heart, and skeletal muscle. 11 Involvement of GUCY2F in the causation of MR seems unlikely, considering that its expression is restricted to a particular subtype of retinal cells, at least in mouse and rhesus monkey. 40 41 A distinct dysmorphic phenotype is associated with MR in our two families.…”

Section: Discussionmentioning

confidence: 99%

“…10 After the original publication, clinical re-evaluation of the family showed alterations of cardiac rhythm and morphology on echocardiography. 11 To elucidate the molecular basis of this complex syndrome, we cloned three genes from the deleted region: FACL4, 12 AMMECR1, 13 and KCNE1L, 11 recently renamed KCNE5. 14 Now we report the characterisation of the deletion, which extends for about 2 Mb, and the identification of a second family which bears a smaller deletion of about 1 Mb.…”

mentioning

confidence: 99%

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Alport syndrome and mental retardation: clinical and genetic dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR)

Meloni

2002

Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Alport syndrome and mental retardation: clinical and genetic dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR)

Meloni

2002

Journal of Medical Genetics

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“…What are possible explanations for the differences between the data presented in previous reports [11,12] and our results? Technical and methodological hypoplasia, and elliptocytosis) [39]. To adapt KCNQ1 channels to the variable biological needs, the function of the pore-forming KCNQ1 alpha subunit is modified by small beta subunits (KCNE1-5) which regulate biophysical properties, pharmacology, and regulation of the channel complex [3,6,7,18,20,31,40].…”

Section: Ph-induced Conversion Of Biophysical Properties Of Hkcne1/hkmentioning

confidence: 99%

KCNE Beta Subunits Determine pH Sensitivity of KCNQ1 Potassium Channels

Heitzmann¹,

Koren²,

Wagner

et al. 2007

Cell Physiol Biochem

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Background/Aims: Heteromeric KCNEx/KCNQ1 (=KvLQT1, Kv7.1) K⁺ channels are important for repolarization of cardiac myocytes, endolymph secretion in the inner ear, gastric acid secretion, and transport across epithelia. They are modulated by pH in a complex way: homomeric KCNQ1 is inhibited by external acidification (low pH_e); KCNE2/KCNQ1 is activated; and for KCNE1/KCNQ1, variable effects have been reported. Methods: The role of KCNE subunits for the effect of pH_e on KCNQ1 was analyzed in transfected COS cells and cardiac myocytes by the patch-clamp technique. Results: In outside-out patches of transfected cells, hKCNE2/hKCNQ1 current was increased by acidification down to pH 4.5. Chimeras with the acid-insensitive hKCNE3 revealed that the extracellular N-terminus and at least part of the transmembrane domain of hKCNE2 are needed for activation by low pH_e. hKCNE1/hKCNQ1 heteromeric channels exhibited marked changes of biophysical properties at low pH_e: The slowly activating hKCNE1/hKCNQ1 channels were converted into constitutively open, non-deactivating channels. Experiments on guinea pig and mouse cardiac myocytes pointed to an important role of KCNQ1 during acidosis implicating a significant contribution to cardiac repolarization under acidic conditions. Conclusion: External pH can modify current amplitude and biophysical properties of KCNQ1. KCNE subunits work as molecular switches by modulating the pH sensitivity of human KCNQ1.

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“…Kv␤ subunits (12). KCNE proteins are auxiliary subunits of at least five members, KCNE1 to KCNE5 (13,14). Each KCNE subunit consists of a single transmembrane segment.…”

mentioning

confidence: 99%

Desensitization of Chemical Activation by Auxiliary Subunits

Gao

Xiong

Sun

et al. 2008

Journal of Biological Chemistry

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Chemical openers for KCNQ potassium channels are useful probes both for understanding channel gating and for developing therapeutics. The five KCNQ isoforms (KCNQ1 to KCNQ5, or Kv7.1 to Kv7.5) are differentially localized. Therefore, the molecular specificity of chemical openers is an important subject of investigation. Native KCNQ1 normally exists in complex with auxiliary subunits known as KCNE. In cardiac myocytes, the KCNQ1-KCNE1 (IsK or minK) channel is thought to underlie the I Ks current, a component critical for membrane repolarization during cardiac action potential. Hence, the molecular and pharmacological differences between KCNQ1 and KCNQ1-KCNE1 channels have been important topics. Zinc pyrithione (ZnPy) is a newly identified KCNQ channel opener, which potently activates KCNQ2, KCNQ4, and KCNQ5. However, the ZnPy effects on cardiac KCNQ1 potassium channels remain largely unknown. Here we show that ZnPy effectively augments the KCNQ1 current, exhibiting an increase in current amplitude, reduction of inactivation, and slowing of both activation and deactivation. Some of these are reminiscent of effects by KCNE1. In addition, neither the heteromultimeric KCNQ1-KCNE1 channels nor native I Ks current displayed any sensitivity to ZnPy, indicating that the static occupancy by a KCNE subunit desensitizes the reversible effects by a chemical opener. Sitedirected mutagenesis of KCNQ1 reveals that residues critical for the potentiation effects by either ZnPy or KCNE are clustered together in the S6 region overlapping with the critical gating determinants. Thus, the convergence of potentiation effects and molecular determinants critical for both an auxiliary subunit and a chemical opener argue for a mechanistic overlap in causing potentiation.

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KCNE1-like Gene Is Deleted in AMME Contiguous Gene Syndrome: Identification and Characterization of the Human and Mouse Homologs

Cited by 67 publications

References 12 publications

Alport syndrome and mental retardation: clinical and genetic dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR)

Alport syndrome and mental retardation: clinical and genetic dissection of the contiguous gene deletion syndrome in Xq22.3 (ATS-MR)

KCNE Beta Subunits Determine pH Sensitivity of KCNQ1 Potassium Channels

Desensitization of Chemical Activation by Auxiliary Subunits

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