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Heterozygous truncating mutation in the human homeobox gene GSH2 has no discernable phenotypic effect
  1. J G Dauwerse1,
  2. C E M de Die-Smulders2,
  3. E Bakker1,
  4. M H Breuning1,
  5. D J M Peters1
  1. 1Center of Human and Clinical Genetics, Leiden University Medical Centre, The Netherlands
  2. 2Department of Clinical Genetics, Academic Hospital Maastricht, The Netherlands
  1. Correspondence to:
 Dr D J M Peters, Center of Human and Clinical Genetics, Leiden University Medical Centre, Sylvius Laboratory, Wassenaarseweg 72, 2333AL Leiden, The Netherlands;
 d.j.m.peters{at}lumc.nl

https://doi.org/10.1136/jmg.39.9.686

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    Mutations in transcription factors with homeobox domains have been identified in a number of developmental disorders, for instance, mutations in PAX6 have been identified in patients with aniridia, mutations in HOX13 in patients with synpolydactyly, and mutations in MSX2 in patients with Boston-type craniosynostosis.1

    The mouse GSH2 gene, like the related GSH1 gene, encodes a homeodomain containing gene that is homologous to the Drosophila intermediate neuroblasts defective (ind) gene.2 In situ hybridisation of GSH2 showed a dynamic, developmentally regulated, spatial and temporal expression pattern.3 Transcripts are particularly abundant in the hindbrain and in the ventral domain of the forebrain.3GSH2 is a downstream target of sonic hedgehog (SHH) and is probably a key regulator in downstream SHH patterning in the ventral forebrain. Mice lacking GSH2 show profound defects in telencephalon development.4 Comparing mice lacking functional alleles of either GSH2 or PAX6 indicated complementary roles for these two genes in dorsoventral patterning of the telencephalon.5

    METHODS

    In a search for a developmental gene on chromosome 4q12, we identified the human homologue of the GSH2 gene. To do so, we performed inter-Alu PCR on yeast artificial chromosome clone 303b3 (CEPH megaYAC6) that by FISH was mapped to the chromosome 4q12 region. With these PCR products, we isolated cosmid 232G12 from a chromosome 4 cosmid library7 and PAC clones pDJ194i7 and pDJ200G9 from the RPC1 PAC library.8 The sequences initially generated on fragments of the cosmid showed homology with BAC clone RP11-56d20, a clone partially sequenced by the …

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