LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy.

Abstract

Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat (LRR) and C-terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype-phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed.

• Authors: Carlo Nobile, Roberto Michelucci, Simonetta Andreazza, Elena Pasini, Silvio C E Tosatto, Pasquale Striano
• Journal: Human mutation (Hum Mutat) Vol. 30 Issue 4 Pg. 530-6 (Apr 2009) ISSN: 1098-1004 [Electronic] United States
• PMID: 19191227 (Publication Type: Journal Article, Review)
• Copyright: (c) 2009 Wiley-Liss, Inc.

Chemical References

• Intracellular Signaling Peptides and Proteins
• LGI1 protein, human
• Proteins

Topics

• Amino Acid Sequence
• Epilepsy, Temporal Lobe (genetics, pathology, physiopathology)
• Genes, Dominant
• Humans
• Intracellular Signaling Peptides and Proteins
• Molecular Sequence Data
• Mutation
• Polymorphism, Genetic
• Protein Structure, Tertiary
• Proteins (chemistry, genetics, physiology)
• Sequence Homology, Amino Acid