title: 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.
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.
authors.affiliation: Genetic Research Centre, National Institute for Research in Reproductive Health (ICMR), Jahangir Merwanji Street, Parel, Mumbai 400 012, India. dasd@nirrh.res.in
authors.forename: Dhanjit Kumar
authors.initials: DK
authors.lastname: Das
authors.forename: Daksha
authors.initials: D
authors.lastname: Sanghavi
authors.forename: Harshavardhan
authors.initials: H
authors.lastname: Gawde
authors.forename: Susan
authors.initials: S
authors.lastname: Idicula-Thomas
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Vasudevan
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002881:Chromosomes, Human, Pair 12 / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D024282:Genes, sry / Q000235:genetics; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007194:India; D007621:Karyotyping; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017384:Sequence Deletion
chemical_list: C509245:DHH protein, human; D053823:Hedgehog Proteins