title: A familial heterozygous null mutation of MET in autism spectrum disorder.
abstract: Autism spectrum disorder (ASD) results from interactions of genetic and environmental factors. The MET proto-oncogene has been identified as a candidate gene for autism susceptibility, and is implicated in neurodevelopment and social brain circuitry. Here, we describe the first case of a familial mutation of MET, consisting of an interstitial genomic deletion removing exons 12 through 15, causing a frameshift and premature stop codon, with evidence of nonsense-mediated mRNA decay. On the other allele, patients carried the C allele of the MET promoter rs1858830 polymorphism, known to decrease MET expression and previously associated with autism susceptibility. The heterozygous mutation was associated with autism in one patient, and language and social impairment in a sibling. Our observations delineate the phenotypic spectrum associated with a clearly defined, very likely complete loss of function mutation of MET. Incomplete penetrance in this family was consistent with MET as a partial susceptibility gene for ASD. Implication of MET in normal and pathological brain development opens new perspectives for understanding the pathophysiology of autism and for eventual therapeutical clues.
authors.affiliation: ULB Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070, Brussels, Belgium.
authors.forename: Nelle
authors.initials: N
authors.lastname: Lambert
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wermenbol
authors.forename: Bruno
authors.initials: B
authors.lastname: Pichon
authors.forename: Sandra
authors.initials: S
authors.lastname: Acosta
authors.forename: Jelle
authors.initials: J
authors.lastname: van den Ameele
authors.forename: Camille
authors.initials: C
authors.lastname: Perazzolo
authors.forename: Diana
authors.initials: D
authors.lastname: Messina
authors.forename: Maria-Franca
authors.initials: MF
authors.lastname: Musumeci
authors.forename: Barbara
authors.initials: B
authors.lastname: Dessars
authors.forename: Anne
authors.initials: A
authors.lastname: De Leener
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.forename: Catheline
authors.initials: C
authors.lastname: Vilain
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: autism spectrum disorder; c-MET; neurodevelopment; social brain