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<p>46,XY disorders of sexual development (46,XY DSD) are conditions characterized by deviations from typical male sex development, which encompasses a broad spectrum of clinical features such as hypospadias, decreased sperm production, dysgenetic testes, bifid scrotum, and the presence of a mature uterus and fallopian tubes. The <i>WWOX</i> gene, which has been implicated in various cancers, is also thought to play a role in sex development, although its involvement in 46,XY DSD remains poorly understood. This study aimed to investigate the <i>WWOX</i> gene in a patient presenting with hypospadias. A 7-month-old male with a history of in-vitro fertilization pregnancy due to male factor and premature birth was referred to our clinic for hypospadias and undescended testicles. The physical examination showed scrotal hypospadias and significant chordee. Chromosome analysis was 46,XY, and the sex-determining region Y protein was positive. Using DNA sequence analysis and protein expression studies, the p.Ala141Thr variant in the <i>WWOX</i> gene was identified. DNA sequencing analysis revealed that the patient is homozygous for this variant, with the father being homozygous (having an infertility history but no physical examination) and the mother heterozygous for the same mutation. Western blot analysis revealed significantly reduced WWOX protein levels in both the proband and father compared to the healthy controls, indicating that the variant impaired protein expression. These findings were consistent with the results from in-silico analyses, which predicted that the p.Ala141Thr substitution disrupts the secondary structure of the WWOX protein, suggesting a functional impact on its activity.</p>

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The Role of WWOX Gene Variant in Hypospadias and 46,XY Disorders of Sexual Development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Yasemin Denkboy Ongen,
  • Havva Tezcan-Unlu,
  • Ufuk Unal,
  • Ecem Efendi-Erdem,
  • Gulsah Cecener,
  • Erdal Eren

摘要

46,XY disorders of sexual development (46,XY DSD) are conditions characterized by deviations from typical male sex development, which encompasses a broad spectrum of clinical features such as hypospadias, decreased sperm production, dysgenetic testes, bifid scrotum, and the presence of a mature uterus and fallopian tubes. The WWOX gene, which has been implicated in various cancers, is also thought to play a role in sex development, although its involvement in 46,XY DSD remains poorly understood. This study aimed to investigate the WWOX gene in a patient presenting with hypospadias. A 7-month-old male with a history of in-vitro fertilization pregnancy due to male factor and premature birth was referred to our clinic for hypospadias and undescended testicles. The physical examination showed scrotal hypospadias and significant chordee. Chromosome analysis was 46,XY, and the sex-determining region Y protein was positive. Using DNA sequence analysis and protein expression studies, the p.Ala141Thr variant in the WWOX gene was identified. DNA sequencing analysis revealed that the patient is homozygous for this variant, with the father being homozygous (having an infertility history but no physical examination) and the mother heterozygous for the same mutation. Western blot analysis revealed significantly reduced WWOX protein levels in both the proband and father compared to the healthy controls, indicating that the variant impaired protein expression. These findings were consistent with the results from in-silico analyses, which predicted that the p.Ala141Thr substitution disrupts the secondary structure of the WWOX protein, suggesting a functional impact on its activity.