Autosomal Dominant Nocturnal Frontal-Lobe Epilepsy: Genetic Heterogeneity and Evidence for a Second Locus at 15q24

Abstract

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis.

Characterization of the genomic structure of the human neuronal nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster and identification of novel intragenic polymorphisms

“…No mutations responsible for ADNFLE were found, indicating that these genes may not be responsible for this syndrome in the analyzed families. Nevertheless, given the genetic heterogeneity of ADNFLE (Oldani et al 1998;Phillips et al 1998), a (Rempel et al 1998) is in light gray. Thick arrows represent Alu sequences.…”

“…In particular, a third locus for ADNFLE was reported on 15q24, a chromosome region that contains the CHRNA5/A3/B4 gene cluster coding for the α5, α3, and 4 subunits, respectively. However, neither the gene nor the mutation involved was identified (Phillips et al 1998).…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…Functional studies of nAchR have produced controversial results, which makes the underlying pathogenic mechanisms unclear. Expression of α4 mutants in human embryonic kidney cells or Xenopus oocytes had various effects, consistent with either gain or loss of function: increased sensitivity to acetylcholine (gain of function), or decreased Ca 2+ potentiation or accelerated desensitization (loss of function) [131,132]. Whereas β2 mutations showed gain of function by increased sensitivity to acetylcholine or slower desensitization [125], the α2 mutation showed gain of function by increased sensitivity to acetylcholine [128].…”

Nocturnal Frontal Lobe Epilepsy

“…Three de novo or inherited CHRNA4 mutations, occasionally associated with mild-to-moderate mental retardation were later reported [15,[30][31][32][33][34][35][36][37]. ADNFLE was quickly recognized as a genetically heterogeneous disorder as most of the described families did not show mutations in the CHRNA4 gene [14,38], and new loci and genes were reported in the following years. In particular, a second locus was identified at chromosome 15q24 in one family [38] and a third locus spanning the pericentromeric region of chromosome 1 was identified in an Italian ADNFLE family [39], the latter containing the gene coding for the β2 subunit of the nACh receptor (CHRNB2) ( Table 1) [40].…”