A classification of genes involved in normal and delayed male puberty

Abstract

Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. It is a major transformational period of life, whose timing is strongly affected by genetic makeup of the individual, along with various internal and external factors. Although the exact mechanism for initiation of the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. We developed a classification of the mechanisms involved in male puberty that allowed placing many genes into physiological context. These include (i) hypothalamic development during embryogenesis, (ii) synaptogenesis where gonadotropin releasing hormone (GnRH) neurons form neuronal connections with suprahypothalamic neurons, (iii) maintenance of neuron homeostasis, (iv) regulation of synthesis and secretion of GnRH, (v) appropriate receptors/proteins on neurons governing GnRH production and release, (vi) signaling molecules activated by the receptors, (vii) the synthesis and release of GnRH, (viii) the production and release of gonadotropins, (ix) testicular development, (x) synthesis and release of steroid hormones from testes, and (xi)the action of steroid hormones in downstream effector tissues. Defects in components of this system during embryonic development, childhood/adolescence, or adulthood may disrupt/nullify puberty, leading to long-term male infertility and/or hypogonadism. This review provides a list of 598 genes involved in the development of HPT axis and classified according to this schema. Furthermore, this review identifies a subset of 75 genes for which genetic mutations are reported to delay or disrupt male puberty.

Case Report: Multiple prolactinomas in a young man with Kallmann syndrome and familial hypocalciuric hypercalcemia

“…Targeted analysis of 36 genes associated with neuroendocrine tumors ( Supplementary Table 1 ), of 63 genes associated with hypogonadotropic hypogonadism ( Supplementary Table 2 ) and TSHZ1 gene associated with isolated congenital anosmia (ICA) did not identify likely pathogenic variants. In an extended panel of 366 candidate genes ( Supplementary Table 3 ) based on their biological function in GnRH neuronal development and action ( 16 ) and in 191 genes ( Supplementary Table 4 ) demonstrated to be downregulated in prolactinoma cells ( 17 ) no pathogenic variants according to ACMG criteria ( 18 ) were identified. Also, no potentially here described disease related de novo variants were identified in the proband.…”

Identification of two compound heterozygous GNRHR mutations in two siblings with congenital hypogonadotropic hypogonadism

“…Some of these genes encode proteins that regulate GnRH neuron differentiation, fate specification, and migration, including fibroblast growth factor receptor 1 ( FGFR1 ), CHD7 , ANOS1 , heparan sulfate 6-O-sulfotransferase 1 ( HS6ST1 ), prokineticin 2 ( PROK2 ), and prokineticin receptor 2 ( PROKR2 ), while other genes encode proteins that regulate GnRH neuron activity and networking, such as KiSS-1 metastasis suppressor ( KISS1 ), KISS1 receptor ( KISS1R ), tachykinin precursor 3 ( TAC3 ), and tachykinin receptor 3 ( TACR3 ), or regulate the direct secretion and action of GnRH, such as GNRHR . 2 6 Mutations in GNRHR are one of the most frequent causes of CHH; 40% of autosomal recessive CHH cases and 16% of sporadic CHH cases are attributable to mutations in GNRHR . 7 Germline mutations in GNRHR were the first genetic mutations identified in patients with CHH, and 56 natural inactivating mutations of this gene have been detected to date.…”