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Human Genetics

, Volume 117, Issue 1, pp 43–53 | Cite as

A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion

  • Ramona Pop
  • Michael V. Zaragoza
  • Mara Gaudette
  • Ulrike Dohrmann
  • Gerd SchererEmail author
Original Investigation

Abstract

Campomelic dysplasia (CD; MIM 114290), an autosomal dominant skeletal malformation syndrome with XY sex reversal, is caused by heterozygous de novo mutations in and around the SOX9 gene on 17q. We report a patient with typical signs of CD, including sex reversal, who was, surprisingly, homozygous for the nonsense mutation Y440X. Since neither parent carried the Y440X mutation, possible mechanisms explaining the homozygous situation were a de novo mutation followed by uniparental isodisomy, somatic crossing over, or gene conversion. As the patient was heterozygous for six microsatellite markers flanking SOX9, uniparental isodisomy and somatic crossing over were excluded. Analysis of intragenic single-nucleotide polymorphisms suggested that the homozygous mutation arose by a mitotic gene conversion event involving exchange of at least 440 nucleotides and at most 2,208 nucleotides between a de novo mutant maternal allele and a wild-type paternal allele. Analysis of cloned alleles showed that homozygous mutant cells constituted about 80% of the leukocyte cell population of the patient, whereas about 20% were heterozygous mutant cells. Heterozygous Y440X mutations, previously described in three CD cases, have been identified in seven additional cases, thus constituting the most frequent recurrent mutations in SOX9. These patients frequently have a milder phenotype with longer survival, possibly because of the retention of some transactivation activity of the mutant protein on SOX9 target genes, as shown by cell transfection experiments. The fact that the patient survived for 3 months may thus be explained by homozygosity for a hypomorphic rather than a complete loss-of-function allele, in combination with somatic mosaicism. This is, to our knowledge, the first report of mitotic gene conversion of a wild-type allele by a de novo mutant allele in humans.

Keywords

Gene Conversion Clubfoot Homozygous Mutation SOX9 Gene Somatic Mosaicism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank the parents of the patient for their interest and support, Maureen Bocian for providing information about the AG family, Victor Steimle for access to and help with the LightCycler, and Michael Wegner for the Neuro2A cell line. We are grateful to Drs. Mary Ann Floyd, Ephrat Levy-Lahad, Joan Paterson, Elie Picard, Rosário Santos, Eva Seemanová, Niels Tommerup, and William Wilcox for submitting samples of and providing information on patients with heterozygous Y440X mutations, and to Maureen Bocian and Jürgen Kohlhase for comments on the manuscript. We appreciate the constructive comments made by one of the reviewers. Francis Poulat, L. Bridgewater, and Benoit de Crombrugghe are acknowledged for providing plasmids. This work was supported by a grant from the Deutsche Forschungsgemeinschaft to G.S. (Sche 194/15–1 and –2).

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Ramona Pop
    • 1
    • 2
    • 4
    • 4
  • Michael V. Zaragoza
    • 3
  • Mara Gaudette
    • 3
  • Ulrike Dohrmann
    • 1
  • Gerd Scherer
    • 1
  1. 1.Institute of Human Genetics and AnthropologyUniversity of FreiburgFreiburgGermany
  2. 2.Faculty for BiologyUniversity of FreiburgFreiburgGermany
  3. 3.Division of Human Genetics, Department of PediatricsUniversity of California IrvineOrangeUSA
  4. 4.Division of Hematology/Oncology, Department of Cancer Biology/PediatricsUniversity of Massachusetts Medical SchoolWorcesterUSA

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