title: Truncation of NHEJ1 in a patient with polymicrogyria.
abstract: Polymicrogyria (PMG) is a common malformation of the human cerebral cortex for which both acquired and genetic causes are known. Although genetic heterogeneity is documented, only one gene is currently known to cause isolated PMG. To clone new genes involved in this type of cerebral malformation, we studied a fetus presenting a defect of cortical organization consisting of a polymicrogyric cortex and neuronal heterotopia within the white matter. Karyotype analysis revealed that the fetus was carrier of a balanced, de novo, chromosomal translocation t(2;7)(q35;p22). Cloning and sequencing of the two translocation breakpoints reveals that the chromosomal rearrangement disrupts the coding region of a single gene, called NHEJ1, Cernunnos, or XLF, in 2q35. The NHEJ1 gene was recently identified as being responsible for autosomal recessive immunodeficiency with microcephaly. Using quantitative PCR experiments, we show that a truncated transcript is expressed in the polymicrogyric patient cells, suggesting a potential dominant negative effect possibly leading to a different phenotype. We performed in situ hybridization on human embryos and showed that the NHEJ1 transcript is preferentially expressed in the telencephalic ventricular and subventricular zones, consistent with the phenotype of the affected individual. In the human adult central nervous system (CNS), NHEJ1 is mainly expressed in the cerebral cortex and in the cerebellum. The association of PMG with the disruption of its transcript suggests that, in addition to its recently uncovered function in the immune system, the NHEJ1 protein may also play a role during development of the human cerebral cortex.
authors.affiliation: INSERM, U491, Faculté de Médecine La Timone, Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lossi
authors.forename: Steven
authors.initials: S
authors.lastname: Lisgo
authors.forename: Chantal
authors.initials: C
authors.lastname: Missirian
authors.forename: Ana
authors.initials: A
authors.lastname: Borges
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.forename: Carla
authors.initials: C
authors.lastname: Fernandez
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardoso
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: Anne
authors.initials: A
authors.lastname: Moncla
authors.forename: Susan
authors.initials: S
authors.lastname: Lindsay
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000002:abnormalities*; D002828:Choristoma / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000002:abnormalities; D006801:Humans; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; D012333:RNA, Messenger; D045643:DNA Repair Enzymes