ESPE Abstracts (2014) 82 P-D-1-2-219

Mutation Analysis of the KISS1, KISS1R, LIN28A, LIN28B, TAC3, and TACR3 Genes in Girls with Central Precocious Puberty

Yoo-Mi Kima, Ja Hye Kimb, Ja Hyang Chob, Jin-Ho Choib & Han-Wook Yoob

aDepartment of Pediatrics, Pusan National University Children’s Hospital, Yangsan, Republic of Korea; bDepartment of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

Background: Central precocious puberty (CPP) is mostly idiopathic, however, familial cases of CPP and evidence of genetic factors on pubertal timing by genome-wide association studies suggested genetic causes of CPP.

Objective and hypotheses: Molecular defects in six genes (KISS1, KISS1R, LIN28A, LIN28B, TAC3, and TACR3) have been known to cause early activation of the hypothalamic-pituitary–gonadal axis. This study investigated genetic defects in these six genes in patients with idiopathic CPP.

Method: This study included 73 girls with breast development before the age of 8 years. Forty-one of them (56.2%) had a family history of CPP. The GnRH stimulation test was performed in all patients and peak LH levels were >5.0 mIU/ml. Also, they showed advanced bone age of at least 1 year relative to chronologic age. Patients with organic brain lesion were excluded in this study. Mutation analyses of the KISS1, KISS1R, LIN28A, LIN28B, TAC3, and TACR3 genes were performed using genomic DNA from peripheral blood leukocytes.

Results: Of the 73 girls who underwent DNA analyses, only one girl (1/73 patients, 1.3%) harbored a heterozygous variant of p.L210I in TACR3, which is located in the third transmembrane domain of the neurokinin B receptor. The p.L210I variant was predicted to be detrimental by web-based prediction programs. It was not detected in the 1000 Genomes database and NHLBI exome variant server. There were no mutations in KISS1, KISS1R, LIN28A, LIN28B, and TAC3.

Conclusion: This study investigated the mutations in candidate genes causing the premature activation of puberty, but only one subject with a heterozygous variant in TACR3 was identified. This result indicates that mutations in these genes are a rare cause of CPP, even in patients with family members with early pubertal timing. Other genetic defects, modifier genes, or environmental influences may play a crucial role in pubertal timing.

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