Truncation ofNHEJ1 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.

PRKDC mutations in a SCID patient with profound neurological abnormalities

“…The patient displayed a marked neurological phenotype substantially more severe than that of previously described LIGIV syndrome or XLF-deficient patients, who normally show mild microcephaly (20,21). The cortical disorganization bears some resemblance to the malformation described in a fetus carrying a balanced translocation that disrupted the gene encoding XLF (43). The fetus had posterior predominant polymicrogyria with extension to the frontal lobe, and small groups of heterotopic neurons in the white matter.…”

A large duplication involving the IHH locus mimics acrocallosal syndrome

“…16 Moreover Cantagrel et al 17 described a patient with hydrocephalus, polymicrogyria and syndactyly of the fingers and toes, who carried a balanced translocation t(2;7)(q36;p22), the breakpoint on chromosome 2 disrupting NHEJ1, a gene also located within the duplicated region in our cases. 17 Seen as the mechanism underlying these phenotypes is rather loss-of-function, we consider NHEJ1 unlikely to be primarily involved in the phenotype seen in this study. We conclude that the duplication's effect on IHH is most likely the main phenotypic determinant in our cases, but we cannot exclude an additive or modifying influence of other genes located in the duplications.…”

Polydactyly in the mouse mutant Doublefoot involves altered Gli3 processing and is caused by a large deletion in cis to Indian hedgehog

“…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.…”