Novel inactivating mutations of the DCAF17 gene in American and Turkish families cause male infertility and female subfertility in the mouse model

Abstract

Loss-of-function DCAF17 variants cause hypogonadism, partial alopecia, diabetes mellitus, mental retardation, and deafness with variable clinical presentation. DCAF17 pathogenic variants have been largely reported in the Middle Eastern populations, but the incidence in American families is rare and animal models are lacking. Exome sequencing in 5 women with syndromic hypergonadotropic hypogonadism from 2 unrelated families revealed novel pathogenic variants in the DCAF17 gene. DCAF17 exon 2 (c.127-1G > C) novel homozygous variants were discovered in 4 Turkish siblings, while 1 American was compound heterozygous for 1-stop gain variant in exon 5 (c.C535T; p.Gln179*) and previously described stop gain variant in exon 9 (c.G906A; p.Trp302*). A mouse model mimicking loss of function in exon 2 of Dcaf17 was generated using CRISPR/Cas9 and showed female subfertility and male infertility. Our results identify 2 novel variants, and show that Dcaf17 plays a significant role in mammalian gonadal development and infertility.

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…The complex clinical picture is characterized by the effects on SNC, but also on the SNP and the neuroendocrine system. Some of the Woodhouse-Sakati traits are hypogonadism, diabetes mellitus, mental retardation, deafness, alopecia, polyneuropathy and extrapyramidal impairment [ 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 ].…”

“…Fibroblasts of patients showed sensitivity to transcriptional blockade induced by actinomycin D, an inhibitor of nucleolar RNA polymerase I [ 186 ]. More recently, a crucial role in mammalian gonadal development and male reproduction has been described for Dcaf17 using a mouse model [ 194 ].…”

Neurodegeneration with Brain Iron Accumulation Disorders: Valuable Models Aimed at Understanding the Pathogenesis of Iron Deposition

“…Dcaf17 constitutive knockout mice showed male infertility due to abnormal sperm development [114]. An additional mouse model generated by CRISPR/Cas9 approach determining loss of function mutation in exon 2 of Dcaf17 , showed also female subfertility in addition to male infertility [115]. This phenotype recapitulates hypogonadism and infertility, which are consistent findings in patients carrying DCAF17 mutations [112] and indicates that this gene plays a role in mammalian gonadal development.…”

In silicoanalysis of coding SNPs and 3′-UTR associated miRNAs inDCAF17gene that may affect the regulation and pathogenesis of Woodhouse-Sakati Syndrome

“…Woodhouse-Sakati Syndrome (WSS, MIM: 241080) is a rare autosomal-recessive multi systemic disorder which is characterized by a combination of hypogonadism, alopecia, Diabetes Mellitus (DM), mental retardation and extrapyramidal signs. (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) It was originally described in a number of consanguineous Saudi families in the Middle East, but has recently been reported in other ethnicities as well. (11,12) Since its original description in 1983, approximately 50 cases have been reported until now.…”