Table 3 Emerging Genes Associated with POI

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]