Universität zu Köln

Pruess, Harald, Gessner, Guido, Heinemann, Stefan H. ORCID: 0000-0002-4144-0251, Rueschendorf, Franz, Ruppert, Ann-Kathrin, Schulz, Herbert, Sander, Thomas and Rimpau, Wilhelm (2019). Linkage Evidence for a Two-Locus Inheritance of LOT-Associated Seizures in a Multigenerational LQT Family With a Novel KCNQ1 Loss-of-Function Mutation. Front. Neurol., 10. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-2295

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Abstract

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Conical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ/dup12; p.R360_0361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LOT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ/dup12 mutation for the LOT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LOTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LOT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pruess, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Gessner, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinemann, Stefan H. UNSPECIFIED orcid.org/0000-0002-4144-0251 UNSPECIFIED Rueschendorf, Franz UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruppert, Ann-Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Sander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Rimpau, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-137463
DOI:	10.3389/fneur.2019.00648
Journal or Publication Title:	Front. Neurol.
Volume:	10
Date:	2019
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-2295
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LONG QT SYNDROME; EPILEPSY; CELF4; TOOL Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13746