Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I

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• 作者：Xavier Daumy^a ; ^b ; ^c ; ¹ ; Mohamed-Yassine Amarouch^d ; ¹ ; ² ; Pierre Lindenbaum^a ; ^b ; ^c ; ^e ; Sté ; phanie Bonnaud^a ; ^b ; ^c ; ^e ; Eric Charpentier^a ; ^b ; ^c ; Beatrice Bianchi^d ; Sabine Nafzger^d ; Estelle Baron^a ; ^b ; ^c ; Swanny Fouchard^d ; Auré ; lie Thollet^d ; Florence Kyndt^a ; ^b ; ^c ; ^e ; Julien Barc^a ; ^b ; ^c ; Solena Le Scouarnec^a ; ^b ; ^c ; Naomasa Makita^f ; Hervé ; Le Marec^a ; ^b ; ^c ; ^e ; Christian Dina^a ; ^b ; ^c ; ^e ; Jean-Baptiste Gourraud^a ; ^b ; ^c ; ^e ; Vincent Probst^a ; ^b ; ^c ; ^e ; Hugues Abriel^d ; ¹ ; ^{Hugues.Abriel@dkf.unibe.ch" class="auth_mail" title="E-mail the corresponding author} ; Richard Redon^a ; ^b ; ^c ; ^e ; ¹ ; Jean-Jacques Schott^a ; ^b ; ^c ; ^e ; ¹ ; ^{jjschott@univ-nantes.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TRPM4 ; Atrio-ventricular block ; PFHBI ; Gain-of-function mutation
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：207
• 期：Complete
• 页码：349-358
• 全文大小：1014 K

文摘

Progressive cardiac conduction disease (PCCD) is one of the most common cardiac conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A, SCN1B, TRPM4, LMNA and GJA5.

Methods and results

In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise role and importance in cardiac conduction and disease is still debated. One novel variant, TRPM4-p.I376T, is carried by the proband of a large French 4-generation pedigree. Systematic familial screening showed that a total of 13 family members carry the mutation, including 10 out of the 11 tested affected individuals versus only 1 out of the 21 unaffected ones. Functional and biochemical analyses were performed using HEK293 cells, in whole-cell patch-clamp configuration and Western blotting. TRPM4-p.I376T results in an increased current density concomitant to an augmented TRPM4 channel expression at the cell surface.

Conclusions

This study is the first extensive NGS-based screening of TRPM4 coding variants in patients with PCCD. It reports the third largest pedigree diagnosed with isolated Progressive Familial Heart Block type I and confirms that this subtype of PCCD is caused by mutation-induced gain-of-expression and function of the TRPM4 ion channel.