IDSD2026 Oral Communication Abstracts Session 2 (8 abstracts)
A new variant in the 3’-UTR of the SRD5A2 gene leads to highly efficient exonisation of an Alu element and contributes to 5α-steroid reductase type 2 deficiency
Ralf Werner 1 , Anna Basina 1,* , Axel Künstner 2 , Sudharsan Agas Chandra Prakash 1 , Kübra Kösem 1 , Alexandra Kulle 3,4 , Nadine C. Hornig 5 , Stefan A. Wudy 6 , Michaela F. Hartmann 6 , Paul-Martin Holterhus 3 , Hauke Busch 2 & Olaf Hiort 1
1Division of Paediatric Endocrinology and Diabetology, Universität zu Lübeck, Lübeck, Germany; 2 Group of Medical Systems Biology, Lübeck Institute of Experimental Dermatology, Universität zu Lübeck, Lübeck, Germany; 3Department of Pediatric Oncology and Rheumatology; Paediatric Endocrinology and Diabetes, University Hospital of Schleswig-Holstein, UKSH, Campus Kiel, Germany; 4Institute of Clinical Chemistry, UKSH, Kiel/Lübeck, Germany; 5Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany; 6Steroid Research & Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany; *present address: Hormone-Hamburg, Hamburg, Germany. Correspondence to: [email protected]
Background: Steroid 5α-reductase deficiency is a rare autosomal recessive condition caused by mutations in the SRD5A2 gene and results in a diminished synthesis of dihydrotestosterone during foetal development. This leads to a severe androgenisation deficit of the external genitalia in people with a 46,XY karyotype. Here we report an adult 46,XY person with clinically confirmed steroid 5α-reductase deficiency.
Methods: Sanger sequencing, whole genome sequencing (WGS), PacBio RNA Isosequencing.
Results: Sanger sequencing revealed a compound heterozygous, pathogenic c.692A>G; p.(His231Arg) variant within the SRD5A2 reading frame and a very rare c.*66T>G variant 66 nt after the canonical stop codon in the 3’-UTR. Sanger sequencing of RT-PCR products from the individual’s derived genital skin fibroblasts revealed that only the maternal pathogenic c.692A>G variant is expressed, while the paternal c.*66T>G variant could not be detected. Short-read whole genome sequencing excluded additional mutations that might affect SRD5A2 expression, both within the SRD5A2 gene promoter or intronic regions. PacBio RNA Isosequencing of patient-derived transcripts revealed that the rare variant c.*66T>G introduces a new strong splice donor site that is spliced to an inverted Alu sequence located 15 kb downstream of the stop codon in the majority of cases. In minor cases this splice donor is spliced to a cryptic splice acceptor 860 nt downstream in the 3’-UTR. In all paternal, but none of the maternal transcripts, we found a new exon junction 66 nt after the stop codon within the 3’-UTR. Mammalian transcripts with an intron excision site >55 nt downstream from a termination codon are subject to degradation by the nonsense-mediated decay (NMD) pathway.
Conclusion: We conclude that the pathogenic maternal c.692A>G variant, together with the NMD-triggered downregulation of the paternal allele, are causative for the observed SRD5A2 deficiency. To our knowledge this is the first description of a mutation-induced Alu exonisation in the 3’-UTR of a DSD related gene.
Volume 118
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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