Defects in Ubiquitination as a Cause of Genitourinary Defects
Abhishek Seth, MD, Joshua Moore, BS, Armando Rivera, PhD, Jill A. Rosenfeld, PhD, Carolina J. Jorgez, PhD.
Baylor College of Medicine, Houston, TX, USA.
BACKGROUND: Given the high prevalence of genitourinary birth defects, it is imperative to elucidate the genetic basis of these disorders. We have discovered copy number variants involving genes encoding components of the E3-ubiquitin-protein ligase complex KCTD13-CUL3 to be significantly associated with hypospadias and cryptorchidism. KCTD13 regulates RHOA expression. RHOA decreases SOX9 expression leading to feminization. Since ubiquitination could play a role in masculinization, we identified and characterized novel single nucleotide variants (SNV) in the KCTD13-CUL3-RHOA-SOX9 pathway. METHODS: To determine the frequency of SNVs in KCTD13, CUL3, SOX9, and RHOA, the Baylor Genetics clinical whole-exome sequencing (BG-WES) database, containing data from ~11500 individuals, was queried. We focused on missense SNVs present in boys with hypospadias and cryptorchidism. To determine if these SNVs were common in the population, the ExAC database containing population-level information about SNV prevalence in ~121322 individuals (including females who are less likely to manifest genitalia defects) was queried. In addition, 40 boys with cryptorchidism and/or hypospadias were Sanger sequenced (SS) for RHOA (5-exons) and KCTD13 (6-exons). RESULTS: Sixty rare variants were reported in BG-WES in SOX9 with 3 SNVs in boys with genitourinary defects. Of these three SNVs, p.P307R was observed in four males with genitourinary defects and was observed only twice in ExAC. Two missense mutations are reported in Met26, p.M26L (novel in a boy with cryptorchidism) and p.M26V (identified in 6 boys with only one having genitourinary defects). p.M26V has 76 reported cases in the population. The BG-WES database contained 15 individuals with RHOA SNVs, and none of them had a genitourinary phenotype; however, SS identified one boy with cryptorchidism to have a potentially damaging novel mutation - p.A174D. Two rare and possibly damaging missense mutations in CUL3 (p.R198S and p.D698N) were identified by BG-WES in boys with cryptorchidism and hypospadias. p.D698N was identified in only one individual from ExAC, but p.R198S is novel and identified in two cryptorchid boys. Two rare and possibly damaging missense mutations (p.E120K and p.P146L) were identified by BG-WES in KCTD13 in boys with genitourinary abnormalities. Also, three mutations (p.H92P, p.A136V and p.L211H) were identified by SS in KCTD13 in boys with cryptorchidism. p.E120K was identified in two males, but only one had a genitourinary phenotype, and the variant is reported three times in ExAC. p.P146L is more common since it was observed in six males by BG-WES (two with cryptorchidism) and ten individuals in the ExAC database. p.H92P and p.L211H are predicted to be damaging and novel. p.A136V is predicted to be benign and found in six individuals in ExAC. CONCLUSIONS: SOX9 mutations have been associated with disorders of sex determination; however, the variants identified in this study have not been associated with genitalia defects. The majority of SNVs were identified in KCTD13 and correlate with the cryptorchid phenotype observed in Kctd13 null mice. This is the first report of mutations in KCTD13, CUL3, and RHOA associated with a human genitourinary phenotype (especially cryptorchidism), indicating that these genes play a critical role in genitalia development.
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