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A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

2010; Oxford University Press; Volume: 163; Issue: 1 Linguagem: Inglês

10.1530/eje-10-0012

1479-683X

Milena Gurgel Teles, Ericka Barbosa Trarbach, Sekoni D. Noel, Gil Guerra‐Júnior, Alexander A.L. Jorge, Daiane Beneduzzi, Suzy D.C. Bianco, Abir Mukherjee, M T M Baptista, Elaine Maria Frade Costa, Margaret de Castro, Berenice B. Mendonça, Ursula B. Kaiser, Ana Claudia Latrônico,

Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Context Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R , have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH). Objective To investigate KISS1R defects in patients with absent or delayed puberty. Patients We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP). Methods The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification. Results One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position −2 to −4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3′ splice acceptor site of intron 2 of KISS1R . The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP. Conclusion Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.