Clinical case seminar: Three new novel point mutations localized within and downstream of high-mobility group-box region in SRY gene in three Indian females with Turner syndrome

Point mutations and deletions in the SRY gene result in XY sex reversal in pure gonadal dysgenesis. To date, a majority of these affect the high-mobility group (HMG) domain of SRY, which plays a key role in its DNA binding activity. We carried out molecular genetics studies in three Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Case 1 demonstrated an insertion of T (thymine) within helix I of HMG box leading to frame shift mutation (N82X). In case 2, insertion of A (adenine) downstream of HMG box resulted in a nonsense frame shift mutation (L159fsX167). These mutations resulted in truncated and altered proteins. In case 3, G>C missense mutation is found at codon 74 within helix I of HMG box (Q74H). No other mutations were found in the SAF gene of these patients. An allele-specific oligonucleotide study further confirmed that these variants are not common polymorphisms. To our knowledge, this is the first time these mutations are described at these codons resulting in mutated SRY proteins. Lack of a second sex chromosome in a majority of cells [mosaic karyotype and mutation(s) in the SRY gene] in these patients may have triggered the short stature.