Truncation of NHEJ1 in a patient with polymicrogyria

Department of Pediatrics, University of Chicago, Chicago, Illinois, United States
Human Mutation (Impact Factor: 5.14). 04/2007; 28(4):356-64. DOI: 10.1002/humu.20450
Source: PubMed


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.

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    • "Indeed, apparently balanced chromosomal rearrangements (translocations or inversions) associated to an abnormal phenotype have allowed to clone numerous disease genes. The incidence of a translocation in newborns is 1:2000 [29] and reciprocal translocations are the most frequently observed structural chromosome abnormalities [5]. "
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    • "This could be attributable to loss of function of any of the genes within the interval for which homozygous mice have not yet been described, and/or to homozygosity for the ectopic Ihh expression defect. Interestingly a recent study reported a human fetus with a balanced de novo translocation t(2;7)(q36;p22) with the chromosome 2 breakpoint interrupting the orthologue of Nhej1 at a position similar to the start of the Dbf deletion (Cantagrel et al., 2007). The consequence of this translocation, as in Dbf, would be to isolate the human IHH gene from possible regulatory sequences present on the opposite side of the NHEJ1 breakpoint. "
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