Two new novel point mutations localized upstream and downstream of the HMG box region of the SRY gene in three Indian 46,XY females with sex reversal and gonadal tumour formation.

The Y chromosome-specific gene SRY is one of the key genes involved in human sex determination. The SRY gene encodes a testis-specific transcription factor that plays a key role in sexual differentiation and development in males and is located on the distal region of the short arm of the Y chromosome. Mutations in SRY gene result in XY sex reversal and pure gonadal dysgenesis. SRY expression initiates a network of gene activity that transforms the undifferentiated gonad, genital ridge into testis. Mutations in the SRY gene have been considered to account for only 10-15% of 46,XY gonadal dysgenesis cases, whereas the majority of the remaining cases may have mutation(s) in the SRY regulatory elements or other genes involved in the sex differentiation pathway. Patients both with gonadal dysgenesis and Y-chromosome presence are at high risk of developing gonadoblastoma. Using PCR, single strand conformational polymorphism (SSCP) and automated DNA sequencing, we analysed the mutations in the SRY gene in three 46,XY sex reversal patients. Two patients demonstrated nucleotide substitution (A-->G) within the open reading frame just outside and upstream of the conserved DNA-binding motif called the high-mobility group (HMG) box, replacing glutamine at codon 57 with arginine. Altered SSCP patterns were also observed in these patients. Histological examination of gonads in patient 1 revealed the formation of gonadoblastoma. Patient 3 demonstrated A-->T substitution which replaces serine at codon 143 with cysteine, just outside but downstream of the HMG box. Results suggest the involvement of SRY gene in sex reversal which further supports the relationship between SRY alterations, gonadal dysgenesis and/or primary infertility.