Table 3 RNA-seq Genes regulated by CBX2.1 and CBX2.2.

CBX2.1 Targets

NTRK1

Involved in testicular development and spermatogenesis.

Genetic knock out mice resulted in a reduced number of testis cords¹⁴⁸.

ANGPTL4

Potential role in lipid metabolism¹⁴⁹

Not reported

CYP19A1

Converts androstenedione to estrone and testosterone to estradiol.

46, XX: virilization of external genitalia¹⁵⁰

DMRT1

Expressed only in the genital ridge. A dose-dependent effect on postnatal testis development.

XY null mice have normal prenatal testis development, but abnormal postnatal testis differentiation. In human: 46, XY testis maldevelopment; 46, XX primary hypogonadism¹⁵¹

EMX2

Homeodomain transcription factor EMX2 is critical for the central nervous system and urogenital development.

Emx2 mutant mice died soon after birth because of the absence of kidneys indicating an essential role in the morphogenesis of the urogenital system⁵⁸.

ESR2

Nuclear receptor transcription factors have a crucial role in reproductive function.

Subfertility and reduced litter sizes and granulosa cell defect³².

KISS1

Implicated in the stimulation of gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion.

KISS1 knock out female mice demonstrated an abnormal reproductive system with abnormal reproductive system phenotype. A clinical case of hypogonadotropic was associated with a loss-of-function of KISS1⁴⁸.

BMP2

BMP2 with FOXL2 ensure expression follistatin in the developing ovary. It amplifies FSH-induced estradiol production in sheep GC.

In mice, BMP2 null mutation is embryonic lethal and foetuses contain a low number of primordial germ cells leading to POF¹²⁹

LHX4

Acts as a transcriptional regulator that is involved in the control of differentiation and development of the pituitary gland.

In human impaired sexual development, Lhx4−/− double-mutant exhibited a specific abnormal placentas phenotype¹⁵².

POF1B

Regulates ovarian function

Assumed to be a causative candidate of POF¹⁵³

FSHR

Follicle stimulating hormone receptor

Mutations in the FSHR cause primary ovarian failure in females and impaired spermatogenesis in males⁵⁰.

CBX2.2 Targets

BMP15

Stimulation of ovarian granulosa cell growth and proliferation and downregulates FSH receptor expression.

In mice: subfertile, in human: ovarian dysgenesis¹⁵⁴.

TEX14

Involvement in spermatogenesis and male fertility.

Male mice infertility⁹⁶

BMP10

Inducer of trophoblast differentiation in human.

Not reported

MAP3K15

Involved in the adrenal pathway

Not reported

HOXA13

Required for morphogenesis of terminal gut and urogenital tract, including Müllerian structures.

Mouse: XX null has hypoplasia of the cervix and vagina. 46, XX human mutation: a hand-footgenital syndrome with uterine malformation⁸⁹.