Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
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Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. / Kruse, Martin; Schulze-Bahr, Eric; Corfield, Valerie; Beckmann, Alf; Stallmeyer, Birgit; Kurtbay, Güven; Ohmert, Iris; Schulze-Bahr, Ellen; Brink, Paul; Pongs, Olaf.
in: J CLIN INVEST, Jahrgang 119, Nr. 9, 9, 2009, S. 2737-2744.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
AU - Kruse, Martin
AU - Schulze-Bahr, Eric
AU - Corfield, Valerie
AU - Beckmann, Alf
AU - Stallmeyer, Birgit
AU - Kurtbay, Güven
AU - Ohmert, Iris
AU - Schulze-Bahr, Ellen
AU - Brink, Paul
AU - Pongs, Olaf
PY - 2009
Y1 - 2009
N2 - Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G-->A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.
AB - Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G-->A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.
M3 - SCORING: Zeitschriftenaufsatz
VL - 119
SP - 2737
EP - 2744
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 9
M1 - 9
ER -
