Affiliation:
1. From the Mayo Clinic, Rochester, MN (D.W.V., D.J.T., M.J.A.); Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (A.A., E.D., J.E.S., H.S.D.); and SUNY State College of Optometry, New York, NY (C.R., M.S.).
Abstract
Background—
An estimated 10% to 15% of sudden infant death syndrome (SIDS) cases may stem from channelopathy-mediated lethal arrhythmias. Loss of the
GJA1
-encoded gap junction channel protein connexin43 is known to underlie formation of lethal arrhythmias.
GJA1
mutations have been associated with cardiac diseases, including atrial fibrillation. Therefore,
GJA1
is a plausible candidate gene for premature sudden death.
Methods and Results—
GJA1
open reading frame mutational analysis was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing on DNA from 292 SIDS cases. Immunofluorescence and dual whole-cell patch-clamp studies were performed to determine the functionality of mutant gap junctions. Immunostaining for gap junction proteins was performed on SIDS-associated paraffin-embedded cardiac tissue. Two rare, novel missense mutations, E42K and S272P, were detected in 2 of 292 SIDS cases, a 2-month-old white boy and a 3-month-old white girl, respectively. Analysis of the E42K victim's parental DNA demonstrated a de novo mutation. Both mutations involved highly conserved residues and were absent in >1000 ethnically matched reference alleles. Immunofluorescence demonstrated no trafficking abnormalities for either mutation, and S272P demonstrated wild-type junctional conductance. However, junctional conductance measurements for the E42K mutation demonstrated a loss of function not rescued by wild type. Moreover, the E42K victim's cardiac tissue demonstrated a mosaic immunostaining pattern for connexin43 protein.
Conclusions—
This study provides the first molecular and functional evidence implicating a
GJA1
mutation as a novel pathogenic substrate for SIDS. E42K-connexin43 demonstrated a trafficking-independent reduction in junctional coupling in vitro and a mosaic pattern of mutational DNA distribution in deceased cardiac tissue, suggesting a novel mechanism of connexin43-associated sudden death.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
74 articles.
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