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  • Title: Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy.
    Author: Di Bonaventura C, Operto FF, Busolin G, Egeo G, D'Aniello A, Vitello L, Smaniotto G, Furlan S, Diani E, Michelucci R, Giallonardo AT, Coppola G, Nobile C.
    Journal: Epilepsia; 2011 Jul; 52(7):1258-64. PubMed ID: 21504429.
    Abstract:
    PURPOSE: To describe the clinical and genetic findings of four families with autosomal dominant lateral temporal epilepsy. METHODS: A personal and family history was obtained from each affected and unaffected subject along with a physical and neurologic examination. Routine electroencephalography and magnetic resonance imaging (MRI) studies were performed in almost all patients. DNAs from family members were screened for LGI1 mutations. The effects of mutations on Lgi1 protein secretion were determined in transfected culture cells. KEY FINDINGS: The four families included a total of 11 patients (two deceased), six of whom had lateral temporal epilepsy with auditory aura. Age at onset was in the second decade of life; seizures were well controlled by antiepileptic treatment and MRI studies were normal. We found two pathogenic LGI1 mutations with uncommonly low penetrance: the R136W mutation, previously detected in a sporadic case with telephone-induced partial seizures, gave rise to the epileptic phenotype in three of nine mutation carriers in one family; the novel C179R mutation caused epilepsy in an isolated patient from a family where the mutation segregated. Another novel pathogenic mutation, I122T, and a nonsynonymous variant, I359V, were found in the two other families. Protein secretion tests showed that the R136W and I122T mutations inhibited secretion of the mutant proteins, whereas I359V had no effect on protein secretion; C179R was not tested, because of its predictable effect on protein folding. SIGNIFICANCE: These findings suggest that some LGI1 mutations may have a weak penetrance in families with complex inheritance pattern, or isolated patients, and that the protein secretion test, together with other predictive criteria, may help recognize pathogenic LGI1 mutations.
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