title: Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria.
abstract: De novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders, ranging from lissencephaly to perisylvian pachygyria. Recently, one family with polymicrogyria (PMG) and mutation in TUBA1A was reported. Hence, the purpose of our study was to determine the frequency of TUBA1A mutations in patients with PMG and better define clinical and imaging characteristics for TUBA1A-related PMG. We collected 95 sporadic patients with non-syndromic bilateral PMG, including 54 with perisylvian PMG and 30 PMG with additional brain abnormalities. Mutation analysis of the TUBA1A gene was performed by sequencing of PCR fragments corresponding to TUBA1A-coding sequences. Three de novo missense TUBA1A mutations were identified in three unrelated patients with PMG representing 3.1% of PMG and 10% of PMGs with complex cerebral malformations. These patients had bilateral perisylvian asymmetrical PMG with dysmorphic basal ganglia cerebellar vermian dysplasia and pontine hypoplasia. These mutations (p.Tyr161His; p.Val235Leu; p.Arg390Cys) appear distributed throughout the primary structure of the alpha-tubulin polypeptide, but their localization within the tertiary structure suggests that PMG-related mutations are likely to impact microtubule dynamics, stability and/or local interactions with partner proteins. These findings broaden the phenotypic spectrum associated with TUBA1A mutations to PMG and further emphasize that additional brain abnormalities, that is, dysmorphic basal ganglia, hypoplastic pons and cerebellar dysplasia are key features for the diagnosis of TUBA1A-related PMG.
authors.affiliation: Institut Cochin, Université Paris-Descartes, CNRS, UMR 8104, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Yoann
authors.initials: Y
authors.lastname: Saillour
authors.forename: Franck
authors.initials: F
authors.lastname: Fourniol
authors.forename: Fiona
authors.initials: F
authors.lastname: Francis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Souville
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Valence
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Jean
authors.initials: J
authors.lastname: Marie Lepage
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Marine
authors.initials: M
authors.lastname: Line Jacquemont
authors.forename: Cherif
authors.initials: C
authors.lastname: Beldjord
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000175:diagnosis / Q000235:genetics*; D054081:Malformations of Cortical Development, Group II / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C533522:TUBA1A protein, human; D014404:Tubulin