title: Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurological Sciences, University of Rome Sapienza, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Di Bonaventura
authors.forename: Francesca F
authors.initials: FF
authors.lastname: Operto
authors.forename: Giorgia
authors.initials: G
authors.lastname: Busolin
authors.forename: Gabriella
authors.initials: G
authors.lastname: Egeo
authors.forename: Alfredo
authors.initials: A
authors.lastname: D'Aniello
authors.forename: Libero
authors.initials: L
authors.lastname: Vitello
authors.forename: Gessica
authors.initials: G
authors.lastname: Smaniotto
authors.forename: Sandra
authors.initials: S
authors.lastname: Furlan
authors.forename: Erica
authors.initials: E
authors.lastname: Diani
authors.forename: Roberto
authors.initials: R
authors.lastname: Michelucci
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Giallonardo
authors.forename: Giangennaro
authors.initials: G
authors.lastname: Coppola
authors.forename: Carlo
authors.initials: C
authors.lastname: Nobile
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D025063:Chromosome Disorders / Q000235:genetics*; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D011506:Proteins