Skip to main content

Table 4 Genes predisposing to nonsyndromic ovarian failure

From: Genes predisposing to syndromic and nonsyndromic infertility: a narrative review

BMP15 (bone morphogenetic protein 15)/GDF9B (growth/differentiation factor 9B) Xp11.22 The gene encodes a member of transforming growth factor-beta superfamily, which plays a role in oocyte maturation and follicular development, through activation of granulosa cells [131]. Several missense mutations reported [131]. Causes ovarian dysgenesis 2 (ODG2), a disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads [132]. May also cause premature ovarian failure 4 (POF4), a disorder in which the ovarian function stops before the age of 40 years and is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol [131, 132].
FIGLA (factor in germline alpha) 2p13.3 FIGLA encodes a germ cell-specific basic helix-loop-helix transcription factor that regulates the expression of the zona pellucida- and oocyte-specific genes, particularly genes involved in folliculogenesis [30, 133]. Missense mutations and deletions that resulted in a frameshift had been reported [134]. FIGLA knockout in female mice prevents formation of primordial follicles, and oocyte numbers drop rapidly after birth [135]. May also cause haploinsufficiency, predisposing to premature ovarian failure 6 (POF6), an ovarian disorder defined as the cessation of ovarian function under the age of 40 years and is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol [134, 136].
NOBOX (newborn ovary homeobox) 7q35 NOBOX encodes a transcriptional regulator with a homeobox motif and is important for early folliculogenesis [137]. Missense mutations in the homeobox domain were observed in infertile Caucasian or African descent [138]. Predisposes to POF [139].
SALL4 (SAL-like 4) 20q13.2 The gene is expressed in the testis and oocytes and secretes putative zinc finger transcription factor that plays a role in the pluripotency of oocytes and maintenance of undifferentiated spermatogonia [38, 140]. Deletions [140]. Predisposes to nonsyndromic POF [140, 141].
FSHβ (follicle-stimulating hormone subunit beta) 11p14.1 This gene encodes the beta subunit of the follicle-stimulating hormone which in association with luteinizing hormone induces egg and sperm production [38, 142]. Tyr76X, Cys51Gly, and Val61X were reported [38]. Causes low FSH and estradiol, and high LH among females, resulting in the absence or incomplete breast development and sterility [143]. Males produce low androgen, leading to low testosterone and azoospermia, but puberty may be normal or absent [38].
HCGβ (human chorionic gonadotrophin) 19q13.3 HCGβ encodes a hormone called HCG which is secreted mainly by the placenta and is important for normal progression of pregnancy by maintaining the production of steroid hormones and other growth factors in the corpus luteum [144]. SNPs named CGB5 p.Val56Leu (rs72556325) and CGB8 p.Pro73Arg (rs72556345) had been reported [145]. Causes low levels of HCG during the first trimester of pregnancy, resulting in miscarriage and ectopic pregnancy [146].
SOHLH1 (spermatogenesis and oogenesis-specific basic helix-loop-helix 1) 9q34.3 This gene encodes one of the testis-specific transcription factors which are essential for spermatogenesis, oogenesis, and folliculogenesis. The protein is necessary for spermatogonial proliferation and differentiation as well as regulates both male and female germline differentiation [147]. Alternatively spliced transcript variants encoding different isoforms have been found for this gene [147]. Causes ovarian dysgenesis 5 (ODG5), a disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism [147]. May also result in spermatogenic failure 32 (SPGF32), a condition that is characterized by non-obstructive azoospermia [148].
SOHLH2 (spermatogenesis and oogenesis specific basic helix-loop-helix 2) 13q13.3 The SOHLH2 is expressed specifically in spermatogonia and oocytes and is required for early spermatogonial and oocyte differentiation [149]. SOHLH2 is a transcription regulator of both male and female germline differentiation and together with SOHLH1 regulates oocyte growth and differentiation [150]. At least 11 mutant variants of SOHLH2 gene have been reported [151]. In particular, two variants, named rs6563386 and rs1328626, were reported by Song et al. [152]. SOHLH2 knockout causes defects in spermatogenesis and oogenesis similar to those in SOHLH1-null mice [149]. May also predispose to PO [151]. Some mutant variants may increase the risk of non-obstructive azoospermia [152], as well as the small testis and testicular atrophy [153].
PGRMC1 (progesterone receptor membrane component 1) Xq24 The gene codes for progestin receptor membrane component 1, which associates with and transports a wide range of molecules, including steroids, and the gene has been demonstrated in zebrafish to function in oocyte maturation and meiosis resumption [154]. Mutant alleles named ecu4, f21, and sa37360 were reported in zebrafish (ZFIN) [154]. PGRMC1 knockout in zebrafish reduces both spawning frequency and the number of embryos produced by females. It also reduces the sensitivity of fully grown immature oocytes to progestin hormone, resulting in a reduced number of oocytes undergoing meiotic maturation [154].
ESR1 (estrogen receptor 1) 6q25.1-q25.2 Estrogen receptor alpha regulates estrogen action in all reproductive tissues. Estrogen signaling mediates leukemia inhibitory factor expression, which is a cytokine critical for blastocyst implantation [155]. A SNP named rs9340799 was reported [155]. Causes estrogen resistance, resulting in absence of pubertal growth and endometriosis-related infertility [155].
HES1 (Hes family bHLH transcription factor 1) 3q29 Hes is expressed in the ovary and encodes transcriptional factors necessary for oocyte survival and maturation [156]. Deletions were reported [156]. HES1 knockout reduces notch signaling and elevates apoptosis, decreasing the number, size, and maturation of oocytes [156].