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Previous Volume 332:1323-1330 May 18, 1995 Number 20 Next

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ABSTRACT

Background Gap junctions are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. Connexin43, the major protein of gap junctions in the heart, is targeted by several protein kinases that regulate myocardial cell–cell coupling. We hypothesized that mutations altering sites critical to this regulation would lead to functional or developmental abnormalities of the heart.

Methods Connexin43 DNA from 25 normal subjects and 30 children with a variety of congenital heart diseases was amplified by the polymerase chain reaction and sequenced. Mutant DNA was expressed in cell culture and examined for its effect on the regulation of cell–cell communication.

Results The 25 normal subjects and 23 of the 30 children with heart disease had no amino acid substitutions in connexin43. All six children with syndromes that included complex heart malformations had substitutions of one or more phosphorylatable serine or threonine residues. Four of these children had two independent mutations, suggesting an autosomal recessive disorder. Five of these children had substitutions of proline for serine at position 364. A seventh child, with a different heart condition, also had a point mutation in connexin43. Transfected cells expressing the Ser364Pro mutant connexin43 sequence showed abnormalities in the regulation of cell–cell communication, as compared with cells expressing normal connexin43.

Conclusions Mutations in the connexin43 gap-junction gene, which lead to abnormally regulated cell–cell communication, are associated with visceroatrial heterotaxia.

Source Information

From the Departments of Physiology (S.H.B.-C., M.M.S.) and Pathology and Human Anatomy (C.W.Z., W.H.F.), Loma Linda University; and the Laboratory for Molecular Cytology, Jerry L. Pettis Memorial Veterans Affairs Medical Center (S.H.B.-C., M.M.S., W.H.F.) — both in Loma Linda, Calif.

Address reprint requests to Mr. Britz-Cunningham at the Department of Physiology, Loma Linda University, Loma Linda, CA 92354.

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N Engl J Med 1995; 333:941-942, Oct 5, 1995. Correspondence

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