Novel homozygous mutations in Desert hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods

Eur J Med Genet. Nov-Dec 2011;54(6):e529-34. doi: 10.1016/j.ejmg.2011.04.010. Epub 2011 Jul 23.

Abstract

Male to female sex reversal in patients with 46,XY karyotype results from the failure of development of testis which may be due to mutations in the SRY gene. Only 10-15% of cases of 46,XY gonadal dysgenesis are accounted for by different types of mutations in the SRY gene. Hence, majority of such patients may have mutations in other genes involved in the testicular differentiation pathway. Besides SRY, other autosomal and X-linked genes are also involved in sexual development during embryogenesis. We describe here the first report from India wherein, two cases of 46,XY complete gonadal dysgenesis that could be attributable to mutations in the Desert hedgehog (DHH) gene. The mutations found in these two patients were a homozygous deletion (c.271_273delGAG) that resulted in deletion of one amino acid (p.D90del) and a homozygous duplication (c.57-60dupAGCC) that resulted in premature termination resulting in non-functional DHH protein. The structure-function implications of the p.D90del mutation were predicted using computational tools. Structural studies on the p.D90del mutant revealed that the mutation could seriously perturb the interaction of DHH with its binding partners. This is the second report in literature showing homozygous mutation in cases with 46,XY complete gonadal dysgenesis.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Chromosomes, Human, Pair 12 / chemistry
  • Chromosomes, Human, Pair 12 / genetics*
  • DNA Mutational Analysis
  • Exons
  • Female
  • Genes, sry / genetics
  • Gonadal Dysgenesis, 46,XY / genetics*
  • Hedgehog Proteins* / genetics
  • Homozygote
  • Humans
  • India
  • Karyotyping
  • Models, Molecular
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Protein Binding
  • Sequence Deletion

Substances

  • DHH protein, human
  • Hedgehog Proteins