A connexin40 mutation associated with a malignant variant of progressive familial heart block type I.
Circ Arrhythm Electrophysiol
; 5(1): 163-72, 2012 Feb.
Article
en En
| MEDLINE
| ID: mdl-22247482
ABSTRACT
BACKGROUND:
Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation. METHODS ANDRESULTS:
We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2±1.7 nS, n=14; Cx40-Q58L, 0.56±0.34 nS, n=14; P<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ≈50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.CONCLUSIONS:
Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fascículo Atrioventricular
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ADN
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Conexinas
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Bloqueo Cardíaco
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Mutación
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Idioma:
En
Revista:
Circ Arrhythm Electrophysiol
Año:
2012
Tipo del documento:
Article
País de afiliación:
Japón