The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD
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ORIGINAL ARTICLE
The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD Floris Levy-Khademi 1,2 Sharon Zeligson3 Eran Lavi2,4 Tehila Klopstock2,3 Boris Chertin2,5 Carmit Avnon- Ziv1 Abdulsalam Abulibdeh2,4 Paul Renbaum3 Tzvia Rosen3 Shira Perlberg-Bengio3 Fouad Zahdeh3 Doron M. Behar6 Ephrat Levy-Lahad2,4 David Zangen2,4 Reeval Segel2,3 ●
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Received: 23 January 2020 / Accepted: 22 April 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords XYDSD Ambiguous genitalia 17βHSD Gene transcription Testosterone ●
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Introduction
These authors contributed equally: Sharon Zeligson, Eran Lavi, Tehila Klopstock, David Zangen, Reeval Segel Supplementary information The online version of this article (https:// doi.org/10.1007/s12020-020-02327-z) contains supplementary material, which is available to authorized users.
Defects in testosterone biosynthesis can lead to XY disorders of sex development (XY DSD). Mutations in the 17 beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) gene encoding a crucial enzyme in testosterone biosynthesis cause a rare form of XY DSD [1]. However, a higher incidence of mutations in HSD17B3 were reported in the highly consanguineous Arab Moslem population in the
* Floris Levy-Khademi fl[email protected]
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* David Zangen zang
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