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.
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.
Authors: P J Schwartz; S G Priori; R Dumaine; C Napolitano; C Antzelevitch; M Stramba-Badiale; T A Richard; M R Berti; R Bloise Journal: N Engl J Med Date: 2000-07-27 Impact factor: 91.245
Authors: William A Paznekas; Simeon A Boyadjiev; Robert E Shapiro; Otto Daniels; Bernd Wollnik; Catherine E Keegan; Jeffrey W Innis; Mary Beth Dinulos; Cathy Christian; Mark C Hannibal; Ethylin Wang Jabs Journal: Am J Hum Genet Date: 2002-11-27 Impact factor: 11.025
Authors: Michael J Ackerman; David J Tester; Gregg S Jones; Melissa L Will; Christopher R Burrow; Mark E Curran Journal: Mayo Clin Proc Date: 2003-12 Impact factor: 7.616
Authors: Ramon Brugada; Kui Hong; Robert Dumaine; Jonathan Cordeiro; Fiorenzo Gaita; Martin Borggrefe; Teresa M Menendez; Josep Brugada; Guido D Pollevick; Christian Wolpert; Elena Burashnikov; Kiyotaka Matsuo; Yue Sheng Wu; Alejandra Guerchicoff; Francesca Bianchi; Carla Giustetto; Rainer Schimpf; Pedro Brugada; Charles Antzelevitch Journal: Circulation Date: 2003-12-15 Impact factor: 29.690
Authors: Henry F Krous; J Bruce Beckwith; Roger W Byard; Torleiv O Rognum; Thomas Bajanowski; Tracey Corey; Ernest Cutz; Randy Hanzlick; Thomas G Keens; Edwin A Mitchell Journal: Pediatrics Date: 2004-07 Impact factor: 7.124
Authors: Luc Leybaert; Paul D Lampe; Stefan Dhein; Brenda R Kwak; Peter Ferdinandy; Eric C Beyer; Dale W Laird; Christian C Naus; Colin R Green; Rainer Schulz Journal: Pharmacol Rev Date: 2017-10 Impact factor: 25.468
Authors: Parveen Sharma; Cynthia Abbasi; Savo Lazic; Allen C T Teng; Dingyan Wang; Nicole Dubois; Vladimir Ignatchenko; Victoria Wong; Jun Liu; Toshiyuki Araki; Malte Tiburcy; Cameron Ackerley; Wolfram H Zimmermann; Robert Hamilton; Yu Sun; Peter P Liu; Gordon Keller; Igor Stagljar; Ian C Scott; Thomas Kislinger; Anthony O Gramolini Journal: Nat Commun Date: 2015-09-25 Impact factor: 14.919