Genetics basis for GnRH-dependent pubertal disorders in humans.

Area of Science:

• Reproductive Endocrinology
• Human Genetics
• Neuroendocrinology

Background:

• Human puberty initiation involves the pulsatile secretion of gonadotropin-releasing hormone (GnRH) and subsequent gonadal activation.
• Genetic factors play a crucial role in regulating the timing and progression of puberty.

Purpose of the Study:

• To review the genetic basis of pubertal disorders, including isolated hypogonadotropic hypogonadism (IHH) and Kallmann syndrome.
• To explore the genetic underpinnings of both delayed and precocious puberty.

Main Methods:

• Literature review of genetic mutations affecting GnRH synthesis, secretion, action, and neuronal development.
• Analysis of gene variants in patients with IHH, Kallmann syndrome, and central precocious puberty.

Main Results:

• Mutations in GNRH1, KISS1R, GNRHR, TAC3, TACR3, KAL1, FGFR1, FGF8, PROK2, PROKR2, and CHD7 are associated with IHH and Kallmann syndrome.
• Genetic defects can disrupt GnRH neuron development, migration, or function, leading to hypogonadism.
• Gain-of-function mutations in kisspeptin pathway genes are linked to central precocious puberty.

Conclusions:

• The genetic landscape of pubertal disorders is complex, featuring monogenic, digenic, and oligogenic inheritance patterns.
• Understanding these genetic mutations provides critical insights into the regulation of human puberty and reproductive axis activation.
• Genetic research is crucial for distinguishing between developmental and functional defects in pubertal onset.