biostudies-literatureHashimoto ASNational Institute for Health Research (NIHR)103427https://www.ebi.ac.uk/biostudies/studies/S-EPMC12167057biostudies-literatureUnknown3<h4>Purpose</h4>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 8 sibships (12 individuals) segregating 5 different homozygous variants of dehydrogenase/reductase 3 <b>(</b> <i>DHRS3</i>), which encodes an embryonically expressed enzyme (short-chain dehydrogenase/reductase 3; also termed SDR16C1) that catalyzes the reduction of retinaldehyde to retinol, limiting excessive RA synthesis.<h4>Methods</h4>We assessed variant pathogenicity using comparative phenotypic and bioinformatic analysis, quantification of <i>DHRS3</i> expression, and measurement of plasma retinoid metabolites.<h4>Results</h4>Five homozygotes from 3 families (1 family segregating a deletion of thGenetics in medicine openIdentification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans.PMC12167057NIHR203308Wilkie AOMTaylor JCPalafoll MIVMoise ARKoch-Hogrebe MMartinez-Gil NYu JLiu TFroukh TJWilliams CCosta-Roger MKane MAWieczorek DVarshosaz PZhao RBanka SPilli NGaudenz KLieberman Hernandez ETwigg SRFTooze RSAbou Jamra RSweeney ERussell JHashimoto ASKnight SJLVillarreal-Molina MTMcGowan SJTrainor PAGattermann FfalseIdentification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans.<h4>Purpose</h4>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 8 sibships (12 individuals) segregating 5 different homozygous variants of dehydrogenase/reductase 3 <b>(</b> <i>DHRS3</i>), which encodes an embryonically expressed enzyme (short-chain dehydrogenase/reductase 3; also termed SDR16C1) that catalyzes the reduction of retinaldehyde to retinol, limiting excessive RA synthesis.<h4>Methods</h4>We assessed variant pathogenicity using comparative phenotypic and bioinformatic analysis, quantification of <i>DHRS3</i> expression, and measurement of plasma retinoid metabolites.<h4>Results</h4>Five homozygotes from 3 families (1 family segregating a deletion of th2025-01-01T00:00:00Z20252026-05-26T20:07:38.254Z2026-05-26T03:07:07.631ZS-EPMC121670574051974810.1016/j.gimo.2025.103427