ADAM23, a Gene Related to LGI1, Is Not Linked to Autosomal Dominant Lateral Temporal Epilepsy

Abstract

Autosomal dominant lateral temporal epilepsy (ADTLE) is an inherited epileptic syndrome characterized by ictal auditory symptoms or aphasia, negative MRI findings, and relatively benign evolution. Mutations responsible for ADLTE have been found in the LGI1 gene. The functions of the Lgi1 protein apparently are mediated by interactions with members of the ADAM protein family: it binds the postsynaptic receptor ADAM22 to regulate glutamate-AMPA currents at excitatory synapses and also the ADAM23 receptor to promote neurite outgrowth in vitro and dendritic arborization in vivo. Because alteration of each of these neuronal mechanisms may underlie ADLTE, ADAM22 and ADAM23 are candidate genes for this syndrome. In a previous work, we excluded a major role of ADAM22 in the aetiology of ADLTE. Here, we performed linkage analysis between microsatellite markers within or flanking the ADAM23 gene and ADLTE in 13 Italian families. The results exclude ADAM23 as major causative gene for ADLTE.

Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors

“…Genetic disorders that are caused by defects in a ligand for a particular receptor are frequently mirrored by disorders in which that receptor is deficient. However, a causative role for ADAM22 and ADAM23 in ADLTE has been questioned in genetic studies of families without LGI1 mutations: direct sequencing of ADAM22 exons revealed no disease-causing mutations [ 34 , 35 ], and linkage analysis with microsatellite markers within or near the ADAM23 gene failed to reveal any significant linkage peak [ 36 ]. The absence of causative mutations in ADAM22 and ADAM23 , however, is not in contrast with their involvement in the molecular pathway underlying ADLTE, and this apparent contradiction can be explained in different ways.…”

Epilepsy with auditory features

“…This perspective is fascinating because other pre- or postsynaptic membrane-bound proteins (ADAM22, ADAM23, and Kv1 channel genes) have been explored before in search for mutations in EAF, but no mutations were detected. 8 – 10 …”

“…No mutation in genes other than LGI1 has been identified so far in EAF. 7 – 10 The advent of next-generation sequencing has made the identification of causal variants possible even in small families. In this study, we describe a comprehensive whole-exome sequencing (WES) approach that enabled us to identify likely pathogenic variants in EAF probands and their affected relatives, demonstrating genetic heterogeneity underlying this epilepsy phenotype.…”