Endocrine Abstracts (2013) 32 P852 | DOI: 10.1530/endoabs.32.P852

A novel mutation in gonadotropin releasing hormone receptor causing delay in puberty in a sporadic case of isolated hypogonadotropic hypogonadism

Misbah Riaz1, Qaiser Mansoor2, Maleeha Akram1, Madiha Shahbaz1, Shaista Aslam3, Shakeel Mirza4, Irfan ullah5, Parveen Akhtar6, Mazhar Qayyum1, Afzaal Ahmed Naseem1, Fahim Tahir7, Muhammad Ismail2 & S S R Rizvi1,8

1Department of Zoology, PMAS Arid Agriculture University, Rawalpindi, Pakistan; 2Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan; 3Department of Zoology, Government College University, Lahore, Pakistan; 4Department of Medicine, Military Hospital, Rawalpindi, Pakistan; 5Pakistan Institute of Sciences (PIMS), Islamabad, Pakistan; 6Department of Pediatrics, Fouji Foundation Hospital, Rawalpindi, Pakistan; 7Department of Reproductive Physiology, National Institute of Health, Islamabad, Pakistan; 8Pakistan Science Foundation, Islamabad, Pakistan.

The signaling of G protein-coupled receptor 54 (GPR54) is a key regulator of the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamic GnRH neurons, whereas GnRH is a crucial neurohormone regulating the secretion of FSH and LH at the time of puberty. The deficiency in the release or action of GnRH leads to hypogonadotropic hypogonadism (HH) characterized by low FSH, LH and testosterone (T) and results in absent or impaired sexual development at puberty. In boys, the absence of the signs of sexual maturation at the age of 15 years is referred to as delayed puberty. Amongst others, mutations in GPR54 and GnRH receptor (GnRHR) are possible causes of HH. The present study was designed to determine the role of mutations in GPR54 and GnRHR genes in causing HH in Pakistani boys. Thirty-one patients with delayed puberty and 31 normal age matched controls were included in the study. Genomic DNA was extracted and amplified by PCR using specific primers for GPR54 and GnRHR splice site exons. Mutations were analyzed by single-stranded conformation polymorphism and/or sequencing. No mutation was identified in GPR54 gene, while two mutations in GnRHR gene were observed in one sporadic case of isolated HH. One was T to G synonymous mutation at nucleotide position 123, which did not cause substitution of valine with any other amino acid. The other mutation at position 101 of the neucleotide was a missense mutation, which substituted serine with phenylalanine at 34th position of the extracellular domain of the GnRHR. This mutation, Ser34Phe, observed in 16 years old boy, caused low concentrations of FSH, LH and T and possibly delayed his puberty. In conclusion, the present study demonstrates that mutations in GnRHR may play a role in delaying male puberty in our local population.