Table 3.

Emerging Genes Associated with POI

Mechanism	Gene	Animal Study	Human Study
Cell-cycle progression; DNA damage response	NUP-107	Knockdown of NUP107 expression led to decreased expression of genes related to estrogen synthesis and receptors on granulosa cells which interferes their sensitivity to FSH [118]	A missense mutation of NUP107 was identified in two sisters with hypergonadotropic hypogonadism [119]
Regulation of ovulation rate; oocyte functional competence	BMPR2	A BMPR2 missense mutation led to aggregates localized at the endoplasmic reticulum in Chinese hamster ovary cell [120] BMPR2 is involved in signal transduction between oocytes and somatic cells [121, 122]	BMPR2 is implicated in folliculogenesis and human ovarian functions [120]
Meiosis	SYCE1	SYCE1 homozygous mutant mice failed to have offspring after 3 months and no follicles or oocytes were observed. Wildtype and heterozygous mutant females were normal [123]	A homozygous missense mutation was identified in two sisters with primary amenorrhea born to a consanguineous parents [63] SYCE1 mutation was found to be underlie an autosomal recessive pattern of POI [124]
	STAG3	STAG3 deficient female mice were found to be sterile with their fetal oocytes arrested at early prophase I. Their oocytes were found to be depleted at 1 week of age [125]	A truncating mutation was identified in two sisters with primary amenorrhea from a consanguineous Lebanese family [126] Two nonsense mutations were identified in two Caucasian sisters presented with POI [127] Two homozygous germline truncation mutations were identified in two sisters diagnosed with POI from a consanguineous Han Chinese family [128]
	MSH4	MSH4 knockout mice presented with meiotic failure and infertility. Many oogonia had been lost at 2-day postnatal detection. Ovaries were found to be small and contain few oocytes at 4 weeks [129]	A homozygous donor splice site mutation was found to cause POI [130]
	MSH5	MSH5 knockout mice was infertile and found to have a markedly reduced size of ovary with no developing follicles. At 2 months of age, no germ cells were found in these mice [131]	A homozygous missense mutation was identified in two Chinese sisters with POI [131]
	DMC1	DMC1 knockout mice presented with aborted oogenesis in embryos and no germ cells were found in adult mice ovary with a markedly reduced size of ovary. At 8-week postnatal evaluation, no follicles were found at any developmental stage [132]	A homozygous missense mutation was identified in a Chinese consanguineous family with POI phenotype [133]
	WDR62	WDR62 knockout mice exhibited meiotic initiation defects [134]	Two missense mutations were detected in two patients with POI [134]
Intercellular communication	GJA4	Connexin-37 is encoded by GJA4 gene. Connexin-37 deficient mice was found to lack mature follicles. They also failed to ovulate and developed numerous inappropriate corpora lutea [135]	A mutation was identified in 2 Caucasian patient with POI [136]
mRNA transcription; Cell growth and differentiation	POLR2C	POLR2C haploinsufficiency was found to disrupt rapid mRNA synthesis required during germ cell proliferation and oocyte maturation process in mice [137, 138]	A nonsense mutation was identified in a family with a dominant inheritance pattern of POI [139]
	POLR3H	Mice with the same missense mutation in POLR3H in patients with POI exhibited impaired reproductive function [140]	A homozygous missense mutation was identified in two unrelated families with idiopathic POI [140]
Germ cell development	MRPS22	Knockdown of MRPS22 in germ cells led to female sterility in drosophila [141]	Two homozygous missense mutations were identified in four females from two independent consanguineous families [141]
	NOTCH2	NOTCH2 knockout mice exhibited defective follicle development [142]	Two missense mutations were identified in patients diagnosed with POI [143]
Autophagy	ATG7/9	Germ-cell specific ATG7-knockout mice exhibited oocyte over-loss during neonatal period [144]	Two heterozygous missense mutations were identified in two patients diagnosed with POI [145]
Apoptosis; Cell cycle progression	TP63	TP63 protects female mice germline integrity during meiotic arrest [146]
Homologous DNA repair	SPIDR	Meiotic RAD51 and DMC1 focus formation in response to DNA damage was found to be reduced in SPIDR knockout mice [147]	A homozygous nonsense mutation was identified in two daughters of consanguineous double first cousin parents of Arab ancestry, both diagnosed with POI [148]