Human Molecular Genetics, Vol 5, 1625-1630, Copyright © 1996 by Oxford University Press
FJ Cameron, RM Hageman, C Cooke-Yarborough, C Kwok, LL Goodwin, DO Sillence and AH Sinclair
Mutations in the gene SOX9 result in the syndrome of campomelic dysplasia
(CD) which includes sex-reversal in 75% of 46,XY affected individuals.
These mutations only affect a single allele of SOX9 suggesting a dominant
mode of inheritance for this syndrome. Consequently, CD and autosomal sex
reversal may result from haploinsufficiency of SOX9. The SOX9 gene maps to
the long arm of human chromosome 17 and translocations in this region also
result in CD. We report a family in which there were three affected
patients, two of whom showed 46,XY sex-reversal. Interestingly, despite all
three patients being heterozygous for a familial mutation in SOX9
(Insertion of a cytosine residue at nucleotide position 1096), their
gonadal phenotypes varied widely. The proband was found to have 46,XY true
hermaphroditism with ambiguous genitalia. The other two sibs were 46,XY and
46,XX, and both had bilateral ovaries with normal female genitalia. The
somatic cells in both parents revealed wild-type SOX9 nucleotide sequences.
However, mutational analysis of the SOX9 gene in the father's germ cells
revealed they were mosaic for mutant and wild-type sequences. This family
is particularly informative as it demonstrates that the same SOX9 mutation
can produce very different 46,XY gonadal phenotypes. The range of gonadal
morphologies observed may be explained by several possible mechanisms such
as variable penetrance of the mutation, increased activity of the
non-mutant SOX9 allele or stochastic environmental factors. These results
also demonstrate that paternal germ cell mosaicism of a mutant SOX9
sequence can result in a CD phenotype amongst his offspring.
ARTICLES
A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, VIC, Australia.
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