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J Am Coll Cardiol. 2017 Jul 18;70(3):358-370. doi: 10.1016/j.jacc.2017.05.039.

Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation.

Author information

1
Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan; Support Center for Women Health Care Professionals and Researchers, Tokyo Women's Medical University, Tokyo, Japan.
2
Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
3
INSERM, CNRS, UNIV Nantes, L'Institut du Thorax, Nantes, France.
4
Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
5
Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University, Tokyo, Japan.
6
Department of Anatomy and Neurobiology, National Defense Medical College, Tokorozawa, Japan.
7
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
8
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
9
INSERM, CNRS, UNIV Nantes, L'Institut du Thorax, Nantes, France; Department of Congenital Cardiology, Evelina London Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
10
CHU Nantes, L'institut du thorax, Service de Cardiologie, Nantes, France.
11
CHRU Brest, Service de Génétique, Brest, France.
12
Fukuoka Prefectural University, Tagawa, Japan.
13
CHU Nantes, Service de Chirurgie Maxillo-Faciale et Stomatologie, Nantes, France.
14
INSERM, CNRS, UNIV Nantes, L'Institut du Thorax, Nantes, France; CHU Nantes, L'institut du thorax, Service de Cardiologie, Nantes, France.
15
Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
16
CHU Nantes, Service de Génétique Médicale, Nantes, France.
17
INSERM, CNRS, UNIV Nantes, L'Institut du Thorax, Nantes, France; CHU Nantes, L'institut du thorax, Service de Cardiologie, Nantes, France. Electronic address: jjschott@univ-nantes.fr.
18
Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: makitan@nagasaki-u.ac.jp.

Abstract

BACKGROUND:

Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often characterized by isolated conduction disturbance of the His-Purkinje system, but it is rarely described as a syndromic form.

OBJECTIVES:

The authors sought to identify the genetic defect in families with a novel bradyarrhythmia syndrome associated with bone malformation.

METHODS:

The authors genetically screened 15 European cases with genotype-negative de novo atrioventricular (AV) block and their parents by trio whole-exome sequencing, plus 31 Japanese cases with genotype-negative familial AV block or sick sinus syndrome by targeted exon sequencing of 457 susceptibility genes. Functional consequences of the mutation were evaluated using an in vitro cell expression system and in vivo knockout mice.

RESULTS:

The authors identified a connexin-45 (Cx45) mutation (p.R75H) in 2 unrelated families (a de novo French case and a 3-generation Japanese family) who presented with progressive AV block, which resulted in atrial standstill without ventricular conduction abnormalities. Affected individuals shared a common extracardiac phenotype: a brachyfacial pattern, finger deformity, and dental dysplasia. Mutant Cx45 expressed in Neuro-2a cells showed normal hemichannel assembly and plaque formation. However, Lucifer yellow dye transfer and gap junction conductance between cell pairs were severely impaired, which suggested that mutant Cx45 impedes gap junction communication in a dominant-negative manner. Tamoxifen-induced, cardiac-specific Cx45 knockout mice showed sinus node dysfunction and atrial arrhythmia, recapitulating the intra-atrial disturbance.

CONCLUSIONS:

Altogether, the authors showed that Cx45 mutant p.R75H is responsible for a novel disease entity of progressive atrial conduction system defects associated with craniofacial and dentodigital malformation.

KEYWORDS:

brachyfacial pattern; congenital atrioventricular block; connexin-45; dentodigital dysplasia; knockout mice; whole-exome sequencing

PMID:
28705318
DOI:
10.1016/j.jacc.2017.05.039
[Indexed for MEDLINE]
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