Identification of locus responsible for familiar mesial temporal lobe epilepsy by linkage study

Author(s)

Cláudia Vianna Maurer Morelli

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2006-07-28

Examining board members

Íscia Teresinha Lopes Cendes; João Pereira Leite; Marilia de Arruda Cardoso Smith; Maria de Fátima Sonati; Li Min Li

• Advisor: Íscia Teresinha Lopes Cendes; Fernando Cendes

Abstract

The association between temporal lobe epilepsy and mesial temporal sclerosis (MTS) has been well established; as well as the use of hippocampal atrophy (HA) on magnetic resonance imaging as an in vivo surrogate marker of MTS. One of the risk factors associated to MTS is childhood prolonged febrile seizures. In 2001, Kobayashi et al., described a type of mesial temporal lobe epilepsy with evident familial recurrence associate with HA but low frequency of febrile seizures, named familial mesial temporal lobe epilepsy (FMTLE). Previous pedigree analysis provided evidence that hippocampal abnormalities may be genetically determined in FMTLE. To determine whether FMTLE can be explained by the involvement of genetic factor we employed complex segregation analysis with the POINTER© software. To investigate candidate genes with significant biological functions related to temporal lobe epilepsy, we genotyped microsatellite markers flanking these relevant genes and performed linkage analysis. In addition, we performed a genome wide search in two large families with 57 individuals, including 27 patients. Our results show the following: i) complex analysis segregation strengthened previous evidence for a genetic predisposition in FMTLE, indicating the presence of a major gene with Mendelian transmission, which could be involved in HA development in these patients; ii) we conclusively ruled out the SCN2A gene as candidate in FMTLE, although the hippocampal lesion in the mutant Scn2a transgenic mouse is similar to that found in our FMTLE patients; iii) linkage analysis showed no evidence that voltage-gated potassium channels are involved in the determination of hippocampal abnormalities in FMTLE; iv) we identified linkage to chromosome 18p11.3-11.2, with a maximum LOD score of 3.63 at ?= 0.0 for the D18S976 marker in a single family (F-10) with 11 affected individuals with HA. Multipoint and haplotype analyses localized the locus within a 6 cM interval flanked by markers D18S976 and D18S452. Furthermore, we failed to find putative pathological mutations related to FMTLE in two candidate genes ZFP161 and TGIF, both mapping within the locus on chromosome 18p11.3-11.2. With our results we have demonstrated the first conclusive evidence that HA may be caused by genetic factors which can have major implications in the study of the pathophysiological mechanisms underlying MTS and its relationship with temporal lobe epilepsy (AU)