The Role of Gap Junctions in Congenital Diseases of the Heart

<p><strong>Background.</strong> 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.</p> <p><strong>Methods.</strong> <em>Connexin43</em> DNA from 25 normal subjects and 30 children with a variety of congenital heart diseases was amplified by the polymerase chain reaction and sequenced. <strong>Mutant DNA</strong> was expressed in cell culture and examined for its effect on the regulation of cell-cell communication.</p> <p><strong>Results. </strong>The 25 normal subjects and 23 of the 30 children with heart disease had no amino acid substitutions in <em>connexin43</em>. 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 seventh child, with a different heart condition, also had a point mutation in connexin43. Transfected cells expressing the Ser364Pro mutant <em>connexin</em>43 sequence showed abnormalities in the regulation of cell-cell communication, as compared with cells expressing normal <em>connexin43.</em></p> <p><strong>Conclusions</strong>. Mutations in the <em>connexin43</em> gap-junction gene, which lead to abnormally regulated cell-cell communication, are associated with visceroatrial heterotaxia.</p>

Name thesis:degree_name

Doctor of Philosophy (Medical Science)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Physiology

Year

1998

Author dc:creator

• Britz-Cunningham, Scott Henry

Contributors dc:contributor

• William H. Fletcher
• Eric C. Beyer
• David Hessinger
• Lawrence Longo
• John Rossi

• Amino Acids, Peptides, and Proteins
• Congenital, Hereditary, and Neonatal Diseases and Abnormalities
• Genetic Phenomena
• Pediatrics
• Physiology
• Heart Defects, Congenital; Abnormalities; Connexins; Gap Junctions; Protein Kinases.

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/1449

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-2221