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A Novel Mutation Ser34Phe in GNRHR causes Hypogonadotropic Hypogonadism during Pubertal Development in Boys

A Novel Mutation Ser34Phe in GNRHR causes Hypogonadotropic Hypogonadism during Pubertal Development in Boys

Misbah Riaz1, Qaiser Mansoor2, Maleeha Akram1, Muhammad Ismail2, Parveen Akhtar3, Shakeel Mirza4, Mazhar Qayyum1, Afzaal Ahmed Naseem1, Faheem Tahir5 and Syed Shakeel Raza Rizvi1*

1Department of Zoology, Pir Mehr Ali Shah Arid Agriculture University, Shamsabad, Murree Road, Rawalpindi, Pakistan
2Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan
3Department of Pediatrics, Fauji Foundation Hospital, Rawalpindi, Pakistan
4Department of Medicine, Military Hospital, Rawalpindi, Pakistan
5Reproductive Physiology, Public Health Laboratories Division, National Institute of Health, Islamabad, Pakistan

*         Corresponding author:


The signaling of G protein-coupled receptor 54 (GPR54) is a key regulator of secretion of gonadotropin-releasing hormone (GnRH), whereas GnRH is a crucial neurohormone regulating the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) at puberty. The deficiency in release or action of GnRH leads to hypogonadotropic hypogonadism (HH) characterized by low FSH, LH and testosterone (T) and absent or impaired sexual development at puberty. Amongst others, mutations in GPR54 and GnRH receptor (GNRHR) are possible causes of HH. This study aimed at identification of mutations in GPR54 and GNRHR genes and their correlation with HH in Pakistani boys. Thirty one boys with delayed puberty and thirty one normal age matched controls were examined. 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 (SSCP) 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. The first was a synonymous substitution mutation of T to G at nucleotide position 123, which did not replace valine with any other amino acid. The other mutation determined at nucleotide position 101, was a missense mutation, which substituted serine with phenylalanine at 34th position of extracellular domain of GNRHR. The Ser34Phe mutation was manifested in phenotypic traits such as low concentrations of FSH, LH and T and delayed puberty. In conclusion, mutations in GNRHR may cause delay in male puberty in Pakistani population.

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Pakistan Journal of Zoology


Pakistan J. Zool., Vol. 56, Iss. 1, pp. 01-501


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