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WDR11 Mutations as A Potential Player of Idiopathic Hypogonadotropic Hypogonadism

The hypothalamic-pituitary-gonadal axis plays animportant
role in the development and progression of the reproductive system
through puberty and adolescence...

As many genes associated with human puberty is also known for their involvement in tumori genesis, WDR11 is also initially recognized as a potential tumor suppressor. The chromosome 10q26 region has been previously contributed to male genital development. In particular WDR11 gene within 10q26 encodes a protein that is a member of the WD repeat protein family to participate in the development and progression of the reproductive system through puberty and adulthood. Recent large analyses add the WDR11 mutations as a potential cause of idiopathic hypogonadotropic hypogonadism (IHH). To date, 14 WDR11 mutations have been shown in IHH patients, 4 of 14 have the second gene mutation and the remaining possess mutation in a single WDR11 gene. The WDR11 protein-signal complex interacts directly with molecules in the development and progression of the reproductive system. We postulate that impaired pubertal development in IHH patients results from a deficiency of proper WDR11 protein interaction in cooperation with additional undetected or known variants.

Mini Review
The hypothalamic-pituitary-gonadal axis plays animportant role in the development and progression of the reproductive system through puberty and adolescence. This neuroendocrine system is initiated by the decapeptide gonadotropin-releasing hormone (GnRH). The GnRH, secreted by the hypothalamus, stimulates the biosynthesis and the release of gonadotropins from the anterior pituitary gland. These gonadotropins, luteinizing hormone and follicle-stimulating hormone, stimulate the gonads to produce sex steroids and gametes [1][2][3]. Disruption to the hypothalamic-pituitarygonadal axis can result in hypogonadotropic hypogonadism through deficient production, secretion or action of the gonadotropins [1,4,5]. Idiopathic hypogonadotropic hypogonadism (IHH) may be associated with normosmia or anosmia; co-occurrence of IHH with anosmia is termed Kallmann syndrome. GnRH neurons originate in the olfactory placode/vomeronasal organ region and migrate into the hypothalamus along olfactory neurons. The Kallmann syndrome results from haled migration of GnRH neurons within the meninges and therefore both GnRH and olfactory neurons do not reach the hypothalamus [6][7][8][9]. Patients with IHH may also manifest additional anomalies or syndrome such as hearing loss, a variety of neurologic defects, and renal agenesis, midline facial defects, dental agenesis [4,[6][7][8][9].
More than 30 genes have been implicated in IHH including 9 genes that cause an overlapping syndrome [9][10][11][12][13][14][15][16]. A large degree of variability in inheritance, penetrance and a number of literatures is also seen in IHH and an increasing body of evidence suggests that this disorder can be caused by variants in more than one gene.
Variants in known IHH genes currently account for only 50% of IHH cases so more genes are yet to be found. The chromosome 10q26 region has previously been associated with male genital development. WDR11 on chromosome 10 encodes a protein that is a member of the WD repeat protein family and participates in a wide variety of cellular processes. Recent large analyses add the WDR11 mutations as a potential cause of IHH. The WDR11 which accounts for 3 % of IHH mutations [17] is not included in recent large analyses and reviews [18,19]. The purpose of this document is DOI: 10.26717/BJSTR.2020.28.004662 21662 to review the known WDR11 mutations to understand as a potential player in IHH.

WDR11 Gene Mutations
To date, 14 WDR11 mutations have been shown in IHH patients, 4 of 14 have the second gene mutation and the remaining possess mutation in a single, as summarized in Table 1. Figure 1 illustrates the positions of theses variants on WDR11 protein structure. The WDR11 mutations have been associated previously with abnormal male genital development including sperm defects and infertility, hypogenitalism, micropenis, cryptorchidism, small testes (cases 1 to 5, and cases 8 to 11)), and abnormal pubertal development due to hypogonadotropic hypogonadism in female (cases 6 and 7).  Table 1). Discussion WDR11 was initially recognized as a potential tumor suppressor and its inactivation has been shown to be a part of the multistep process of glial tumorigenesis and tumor progression [21,22]. One of the common frequent genetic changes in glial tumors is heterozygous loss of chromosome that leads to malignant progression. Damages to 10q region have been observed relatively infrequently in low-grade astrocytomas and oligodendrogliomas.
Many genes human puberty-linked genes are also known for their involvement in tumorigenesis [23]. For instance, hypothalamic expression of certain tumor suppressor genes is overexpressed during puberty or decreased with delayed puberty [24,25]. The KISS1, a tumor metastasis suppressor gene in melanoma and breast carcinomas encodes a peptide ligand of G protein-coupled receptors, which plays a key role in the initiation of puberty [26,27]. KISS1R mutations cause autosomal recessive IHH in consanguineous families [28]. Although WDR11's function is unknown, this gene is predicted to display two ß propellers composed of WD domains. WDR11 protein consists of 12 WD domains and nine of them ( Figure 1) are involved in the genesis of two consecutive ß propellers [17]. Variants that affect WD domains can disrupt the WD function. The changes predicted to flank the WD domains may also play a significant role in IHH. Of 14 hypogonadism patients with WDR11 variants, 4 patients have mutations in two or more genes. We understand that this sample size is too small, and that future researchis needed to elucidate the pathways involved in the digenic mutations, but these findings serve to suggest which genes could interact with each other. Nevertheless, our analysis may indicate that 10 of 14 patients with hypogonadism patients possess mutation in a single WDR11 gene, indicating that the monogenic mutations account for most cases of IHH and hypogonadism.