Details

Autor(en) / Beteiligte

• Antúnez-Argüelles, Erika
• Rojo-Domínguez, Arturo
• Arregui-Mena, Ana Leticia
• Jacobo-Albavera, Leonor
• Márquez, Manlio Fabio
• Iturralde-Torres, Pedro
• Villarreal-Molina, María Teresa

Titel

Compound heterozygous KCNQ1 mutations (A300T/P535T) in a child with sudden unexplained death: Insights into possible molecular mechanisms based on protein modeling

Ist Teil von

• Gene, 2017-09, Vol.627, p.40-48

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Sudden death in a child is a devastating event with important medical implications for surviving relatives. Because it may be the first manifestation of unknown inherited cardiac disease, molecular autopsy can be helpful to determine the cause of death and identify at risk family members. The aim of the study was to perform a molecular autopsy in a seven year-old girl with sudden unexplained death, to find evidence supporting the possible pathogenicity of mutations identified in inherited cardiac disease genes, and to clinically and genetically assess first-degree relatives. DNA from the index case was extracted from umbilical cord cells stored at birth, and DNA of first-degree relatives from blood samples. Targeted sequencing was performed using a Haloplex design including 81 cardiogenes. Possible functional consequences of the mutations were analyzed using protein modeling and structural mobility analyses. The child was compound heterozygous for KCNQ1 variants p.Ala300Thr and p.Pro535Thr. Ala300Thr is known to cause long QT syndrome in the homozygous state, while Pro535Thr is novel and of unknown clinical significance. The father and sibling were Ala300Thr heterozygous, and had normal QTc intervals at rest and during exercise. The asymptomatic mother was heterozygous for Pro535Thr, and showed borderline QTc at rest, but prolonged QTc during exercise. Protein modeling predicted that Ala300Thr alters the mobility profile of the Kv7.1 tetramer and Thr535 disrupts a calmodulin-binding site, probably causing co-assembly or trafficking defects of the mutant monomer. Altogether, the evidence strongly suggests that this child was affected with a recessive form of Romano Ward syndrome. [Display omitted] •Molecular autopsy in sudden unexplained death revealed compound heterozygous KCNQ1 mutations.•Protein modeling predicted the T300 mutation alters tetramer flexibility.•The T535 mutation is predicted to disrupt a calmodulin-binding site.•Defective trafficking of the T535 monomer would simulate a T300 homozygous state.•These predictions are compatible with a severe long QT syndrome phenotype.