Mol. Hum. Reprod. Advance Access originally published online on May 21, 2004
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Molecular Human Reproduction, Vol. 10, No. 7, pp. 521-526, 2004
Molecular Human Reproduction vol. 10 no. 7 © European Society of Human Reproduction and Embryology 2004; all rights reserved
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
1Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi-110 025, India 2CSIRO Health Sciences and Nutrition, Adelaide, Australia 3Division of Molecular Oncology, ICMR (ICPO), Maulana Azad Medical College Campus, Bhadur Shah Zafar Marg, New Delhi-110 002, India 4Division of Reproductive Health & Nutrition, Indian Council of Medical Research, Ansari Nagar, New Delhi, India 5Department of Obstetrics & Gynecology, Lok Nayak Jai Prakash Hospital & Associates, Maulana Azad Medical College Campus, Bhadur Shah Zafar Marg, New Delhi-110 002, India
6 To whom correspondence should be addressed at: Genome Stability Laboratory, CSIRO Health Sciences and Nutrition, Gate No. 13, Kintore Avenue, P.O.Box 10041, Adelaide BC, Adelaide 5000, Australia.; Email: varinderpal.dhillon{at}csiro.aucorresponding
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 AT 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.
Key words: gonadoblastoma/SRY gene/46,XY sex reversal
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