The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD

Floris Levy-Khademi*, Sharon Zeligson, Eran Lavi, Tehila Klopstock, Boris Chertin, Carmit Avnon- Ziv, Abdulsalam Abulibdeh, Paul Renbaum, Tzvia Rosen, Shira Perlberg-Bengio, Fouad Zahdeh, Doron M. Behar, Ephrat Levy-Lahad, David Zangen, Reeval Segel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Purpose: Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated. Methods: We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c. 673G>A mutation. The effect of the mutation on splicing was determined in RNA extracted from the testis of one patient. Results: Three patients presented at ages 0.1, 8 and 0.7 years with ambiguous genitalia and an XY Karyotype. Endocrine workup showed normal cortisol and mineralocorticoid levels with a low testosterone/androstenedione ratio. Whole-exome sequencing, carried out in the first family, revealed a homozygous novel mutation in the HSD17B3 gene: c. 673G>A, p. V225M. The same mutation was found by Sanger sequencing in the third unrelated patient. Haplotype analysis of a 4 Mb region surrounding the HSD17B3 gene on chromosome 9 revealed that the mutation resides on the same allele in all three patients. The mutation, being the first nucleic acid on exon 10, affects splicing and causes exon 10 skipping in one of our patients’ testes. Conclusion: The novel homozygous c. 673G>A, p. V225M mutation in the 17HSDB3 gene is likely a founder mutation and causes severe XY-DSD. It changes a conserved amino acid residue, and also alters 17HSDB3 gene transcription by causing skipping of exon 10, thereby contributing to an imbalance in the relevant protein isoforms and consequently, significant decreased 17HDSB3 enzymatic activity.

Original languageAmerican English
Pages (from-to)650-654
Number of pages5
Issue number3
StatePublished - 1 Sep 2020

Bibliographical note

Funding Information:
This study was supported by a grant from Shaare Zedek medical Center (Mirsky fund, 2018).

Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.


  • 17βHSD
  • Ambiguous genitalia
  • Gene transcription
  • Testosterone


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