Table 2. Current List of Genes Associated with Only Congenital Hypogonadotropic Hypogonadism.
| Gene and protein (alternative names) |
OMIM | Known biological activity | Reversible | Oligogenicity | Inheritance |
|---|---|---|---|---|---|
|
DMXL2 (Rabconnectin-3α) |
616113 | Synaptic protein involved in stimulation and homeostasis of GnRH neurons and gonadotrophs. Also mutated in polyendocrine-polyneuropathy syndrome. | ND | ND | Autosomal recessive |
|
GNRH1 (gonadotropin-releasing hormone 1) |
614841 | Exclusively expressed by GnRH-releasing neurons. Binds to its receptor GnRHR to stimulate HPG axis. | ND | ND | Autosomal recessive |
|
GNRHR (gonadotropin-releasing hormone receptor) |
146110 | G-protein-coupled 7-transmembrane-domain receptor for GnRH, expressed in the gonadotrophs in the pituitary. | Yes | Yes | Autosomal recessive |
|
KISS1 (kisspeptin; metastin) |
614842 | Secreted by the hypothalamic neurons of arcuate and anteroventral periventricular nucleus. Binds to its receptor GPR54 to regulate GnRH neurons. | ND | ND | Autosomal recessive |
|
KISS1R (G-protein-coupled receptor 54) |
614837 | G-protein-coupled receptor for kisspeptin, expressed in hypothalamic GnRH neurons. | ND | Yes | A utosomal recessive/dominant |
|
LEP (leptin) |
614962 | Adipocyte-specific hormone regulating food intake, energy balance and fat metabolism. Associated with obesity. | ND | ND | Autosomal recessive |
|
LEPR (leptin receptor) |
614963 | Single-transmembrane-domain receptor for leptin. Preferentially expressed in hypothalamus. | ND | ND | ND |
|
NR0B1(DAX1) (nuclear receptor subfamily 0, group B) |
300200 | Negative regulator of retinoic acid receptor. Mutated in X-linked congenital adrenal hypoplasia with HH. | ND | ND | X-linked recessive |
|
OTUD4 (OTU domain-containing protein 4) |
611744 | De-ubiquitinase found to be mutated in Gordon Holmes syndrome, a hypogonadism associated with cerebellar ataxia. | ND | ND | Autosomal recessive |
|
PCSK1 (proprotein convertase-1) |
162150 | Required for processing of various pre-hormones including proopiomelanocortin, proinsulin, and proglucagon. | ND | ND | ND |
|
PNPLA6 (patatin-like phospholipase domain-containing protein 6) |
603197 | Catalyzes the de-esterification of membrane phosphatidylcholine. Also mutated in Gordon Holmes and Boucher-Neuhauser syndrome. | ND | ND | Autosomal recessive |
|
RNF216 (ring finger protein 216) |
609948 | Zinc finger protein that binds and inhibits TNF and NF-κB. Also mutated in Gordon Holmes syndrome. | ND | ND | Autosomal recessive |
|
TAC3 (tachykinin 3; neurokinin B, neuromedin-K) |
614839 | Secreted in the hypothalamic neurons of arcuate nucleus. Binds to its receptor TACR3 to regulate the secretion and homeostasis of GnRH neurons. | Yes | Yes | Autosomal recessive |
|
TACR3 (tachykinin receptor 3; neurokinin B receptor, neuromedin-K receptor) |
614840 | G-protein-coupled receptor for TAC3. Expressed in hypothalamic GnRH neurons to regulate secretion and homeostasis of GnRH. | Yes | Yes | Autosomal recessive |
OMIM, Online Mendelian Inheritance in Man; ND, not determined; HPG, hypothalamic-pituitary-gonadal; GPR54, G-protein-coupled receptor 54; DAX1, dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; HH, hypogonadotropic hypogonadism; TNF, tumor necrosis factor; NF-κB, nuclear factor-κB.