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Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure

Dixit, Hridesh MSc1; Rao, Lakshmi K MSc1; Padmalatha, Venkata MSc1; Kanakavalli, Murthy MSc1; Deenadayal, Mamatha MD2; Gupta, Nalini MD3; Chakravarty, Baidyanath MO, FROG, DSc3; Singh, Lalji PhD, DSc1

doi: 10.1097/01.gme.0000184424.96437.7a

Objective: To establish the risk associated with mutations in the coding region of GDF9 gene in Indian women with ovarian failure.

Design: This case-control study was designed for mutational analysis of the GDF9 coding region in a cohort of women with premature ovarian failure (n = 127), primary amenorrhea (n = 58), and secondary amenorrhea (n = 10) compared with controls (n = 220).

Results: This case-control study revealed eight mutations in the GDF9 gene, including five novel mutations: c.1-8C>T, c.199A>C (p.Lys67Glu), c. 205C>T, c.646G>A (p.Val216Mat), and c.1353C>T, and three documented mutations: c.398-39C>G, c.447C>T, and c.546G>A. Missense mutation c.199A>C was present in 4 of 127 premature ovarian failure (POF) cases and 1 of 10 secondary amenorrhea cases. The c.646G>A mutation was present in two POF cases. Both missense mutations were absent in controls. Genotype distribution of c.447C>T was significantly different in POF cases than controls (χ2 = 5.93, P = 0.05). We chose two frequent single-nucleotide polymorphisms (c.398-39C>G, c.447C>T) for haplotyping and found that the C-T haplotype was significantly higher in patients (P = 0.03), whereas the C-C haplotype was representative of the control group.

Conclusions: We report two rare missense mutations, c.199A>C and c.646G>A, which are associated with ovarian failure. The presence of the c.447>T mutation might indicate a higher risk for POF. Haplotype C-T was significantly associated with ovarian failure, whereas the C-C haplotype was representative of the control group.

Growth differentiation factor 9 (GDF9) is an oocyte-derived growth factor that plays a crucial role in follicle development. This study revealed an association between two rare missense mutations, c.199A>C (p.Lys67Glu) and c.646Gr>A (p. Val216mar), in Indian women with ovarian failure.

From the 1Centre for Cellular and Molecular Biology, Hyderabad, India; 2Infertility Institute and Research Centre, Hyderabad, India; and 3Institute of Reproductive Medicine, Kolkata, India.

Received July 30, 2004; revised and accepted March 7, 2005.

This study was supported by a grant from the Indian Council of Medical Research, New Delhi. H.D. was supported by fellowship from the Council of Scientific and Industrial Research (CSIR), Government of India.

Address correspondence to: Dr. Lalji Singh, Director, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad-500007, A.P., India. E-mail:

©2005The North American Menopause Society