Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans

Journal article

Purpose

Signaling by the morphogen all-trans-retinoic acid (RA) is critical for embryonic development, during which its tissue concentration must be tightly regulated. We investigated eight sibships (12 individuals) segregating five different homozygous variants of DHRS3, which encodes an embryonically expressed enzyme (short-chain dehydrogenase/reductase 3; also termed SDR16C1) that catalyses the reduction of retinaldehyde to retinol, limiting excessive RA synthesis.

Methods

We assessed variant pathogenicity using comparative phenotypic and bioinformatic analysis, quantification of DHRS3 expression, and measurement of plasma retinoid metabolites.

Results

Five homozygotes from three families (one family segregating a deletion of the promoter and 5′-untranslated region (UTR) of DHRS3, the other two a missense variant p.(Val171Met)), manifested a congruent phenotype including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals) and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from two homozygotes for the promoter/5′-UTR deletion was 90-98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared to wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared to controls and heterozygous relatives. Three additional homozygous missense variants of DHRS3 [p.(Val110Ile), p.(Gly115Asp), p.(Glu244Gln)] were shown to reduce catalytic activity in vitro and/or in vivo, but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.

Conclusion

We define a novel developmental syndrome associated with biallelic hypomorphic variants in DHRS3; careful assessment of individual variants is required to establish a causal link to phenotype.

Authors: Hashimoto, AS; Yu, J; Williams, C; Gaudenz, K; Varshosaz, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Genetics in Medicine Open
• Volume: 3
• Article number: 103427
• Publication date: 2025-03-29
• Acceptance date: 2025-03-26
• DOI: 10.1016/j.gimo.2025.103427
• EISSN: 2949-7744
• Language: English
• Keywords: 5'-untranslated region; atrial septal defect; craniosynostosis; retinaldehyde; retinoic acid; vitamin A; scoliosis; non-coding variant