Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. N. Phelan, E. Williams, S. Cardamone, M. Lee, M. Creighton, G. Rumsby, G.S. Conway, Screening for mutation in 17 β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilized 46, XY disorders of sex development. Eur. J. Endocrinol. 172, 745–751 (2015)

    Article  CAS  Google Scholar 

  2. A. Rosler, S. Silverstein, D.Abelovich, A (R80Q) mutation in 17 β-hydroxysteroid dehydrogenase Type 3 gene among Arabs of Israel is associated with pseudo hermaphroditism in males and normal asymptomatic females. J. Clin. Endocrinol. Metabol 81, 1827–1831 (1996)

    CAS  Google Scholar 

  3. U. Goebelsmann, R. Horton, J.H. Mestman, J.J. Arce, Y. Nagata, R.M. Nakamura, I.H. Thorneycroft, D.R. Mishell, Male pseudo hermaphroditism due to testicular 17 β-hydroxysteroid dehydrogenase deficiency. J. Clin. Endocrinol. Metab. 36, 867–878 (1973)

    Article  CAS  Google Scholar 

  4. A. Rosler, A. Belanger, F. Labrie, Mechanisms of Androgen production in male pseudo hermaphroditism due to 17 β-hydroxysteroid dehydrogenase deficiency. J. Clin. Endocrinol. Metab. 75, 773–778 (1992)

    CAS  PubMed  Google Scholar 

  5. A. Boehmer, A.O. Brinkmann, L.A. Sandkuijl, D.J. Halley, F. Martinus, N.S. Andersson, F.H. De Jong, H. Kayserili, M.A. De Vroede, B.J. Otten et al. 17 β-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J. Clin. Endocrinol. Metab. 84, 4713–4721 (1999)

    CAS  PubMed  Google Scholar 

  6. N. Moghrabi, I.A. Hughes, H.A. Dunaif, S. Andersson, Deleterious missense mutations and silent polymorphism in the human 17 β-hydroxysteroid dehydrogenase 3 gene (HSD17B3). J. Clin. Endocrinol. Metab. 83, 2855–2860 (1998)

    CAS  PubMed  Google Scholar 

  7. M.D. Omrani, T. Adamovic, U. Grandell, S. Saleh-Garhari, A. Nordenskjold, 17-β-hydroxysteroid dehydrogenase type 3 deficiency in three adult Iranian siblings. J. Sex. Dev. 5, 273–276 (2011)

    Article  CAS  Google Scholar 

  8. B. Ben Rhouma, N. Belguith, M. Feki Mnif, T. Kamoun, N. Charfi, M. Kamoun, F. Abdelhedi, M. Hachicha, H. Kamoun, M. Abid, F. Fakhfakh, A novel nonsense mutation in HSD17B3 gene in a Tunisian patient with sexual ambiguity. The. J. Sex. Med. 10, 2586–2589 (2013)

    Article  Google Scholar 

  9. A. Alikasifoglu, D. Vuralli, O. Hiort, N. Gonc, A. Ozon, N. Kandemir, Severe undervirilization in a 46, XY case due to a novel mutation in HSD17B3 gene. J. Clin. Res. Pediatr. Endocrinol. 7, 249–252 (2015)

    Article  Google Scholar 

  10. R.T. Engeli, M. Tsachaki, H.A. Hassan, C.P. Sager, M.L. Essawi, Y.Z. Gad, Biochemical analysis of four missense mutations in the HSD17B3 gene associated with 46, XY disorders of sex development in Egyptian patients. The. J. Sex. Med. 14, 1165–1174 (2017)

    Article  Google Scholar 

  11. S.A. Wudy, M.F. Hartmann, Gas chromatography–mass spectrometry profiling of steroids in times of molecular biology. Horm. Metab. Res. 36, 415–422 (2004)

    Article  CAS  Google Scholar 

  12. ExAC Browser. http://exac.broadinstitute.org/. Accessed 19 Jul 2017

  13. ClinVar. https://www.ncbi.nlm.nih.gov/clinvar/. Accessed 19 Jul 2017

  14. dbSNP Home Page. https://www.ncbi.nlm.nih.gov/projects/SNP/. Accessed 19 Jul 2017

  15. F. Pagani, F.E. Baralle, Genomic variants in exons and introns: identifying the splicing spoilers. Nat. Rev. Genet. 5, 389–396 (2004)

    Article  CAS  Google Scholar 

  16. X. Jian, E. Boerwinkle, X. Liu, In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res. 42, 13534–13544 (2014)

    Article  CAS  Google Scholar 

  17. Y.S. Lee, J.M.W. Kirk, R.G. Stanhope, D.I. Johnston, S. Harland, R.J. Auchus, S. Andersson, L.A. Hughest, Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. Clin. Endocrinol. 67, 20–28 (2007)

    Article  CAS  Google Scholar 

  18. R.L. Batista, M. Inacio, I.J.P. Arnold, N.L. Gomes, J.A. Diniz Faria, D.R. De Mores, E.M. Frade Coste, S. Dominice, B.B. Mendonca, Psychosexual aspects, effects of prenatal androgen exposure, and gender change in 46, XY disorders of sex development. J. Clin. Endocrinol. Metab. 104, 1160–1170 (2019)

    Article  Google Scholar 

  19. D.J. Gross, H. Landau, G. Kohn, A. Farkas, E. Elrayyese, R. El-Shawwa, E.E. Lasch, A. Rosler, Male pseudo hermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: gender reassignment in early infancy. Acta Endocrinol. 112, 238–246 (1986)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Author notes

  1. These authors contributed equally: Sharon Zeligson, Eran Lavi, Tehila Klopstock, David Zangen, Reeval Segel

Authors and Affiliations

  1. Division of Pediatric Endocrinology, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel

    Floris Levy-Khademi & Carmit Avnon- Ziv

  2. The Hebrew University School of Medicine, Jerusalem, Israel

    Floris Levy-Khademi, Eran Lavi, Tehila Klopstock, Boris Chertin, Abdulsalam Abulibdeh, Ephrat Levy-Lahad, David Zangen & Reeval Segel

  3. The institute of Medical Genetics, Shaare Zedek Medical Center, Jerusalem, Israel

    Sharon Zeligson, Tehila Klopstock, Paul Renbaum, Tzvia Rosen, Shira Perlberg-Bengio, Fouad Zahdeh & Reeval Segel

  4. Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    Eran Lavi, Abdulsalam Abulibdeh, Ephrat Levy-Lahad & David Zangen

  5. Department of Pediatric Urology, Shaare Zedek Medical Center, Jerusalem, Israel

    Boris Chertin

  6. Gene by Gene, Genomic Research Center, Houston, Texas, USA

    Doron M. Behar

Authors
  1. Floris Levy-Khademi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon Zeligson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eran Lavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tehila Klopstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Boris Chertin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carmit Avnon- Ziv
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Abdulsalam Abulibdeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul Renbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tzvia Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shira Perlberg-Bengio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fouad Zahdeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Doron M. Behar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ephrat Levy-Lahad
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Zangen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Reeval Segel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Floris Levy-Khademi or David Zangen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Levy-Khademi, F., Zeligson, S., Lavi, E. et al. The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD. Endocrine 69, 650–654 (2020). https://doi.org/10.1007/s12020-020-02327-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-020-02327-z

Keywords

Search

Navigation