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

## TL;DR

This study identifies a new human developmental disorder caused by mutations in the DHRS3 gene, which disrupts retinoic acid regulation during embryonic development.

## Contribution

The paper reports a novel retinoic acid embryopathy caused by biallelic DHRS3 deficiency and establishes its clinical and biochemical features.

## Key findings

- DHRS3 deficiency leads to reduced retinol and elevated retinoic acid levels in patients.
- Biallelic hypomorphic DHRS3 variants are associated with a distinct developmental syndrome including craniosynostosis and heart defects.
- Not all DHRS3 variants cause the same phenotype, emphasizing the need for variant-specific analysis.

## Abstract

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 (DHRS3), 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.

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

Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5′-untranslated region of DHRS3, the other 2 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 2 homozygotes for the promoter/5′-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with 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 with controls and heterozygous relatives. Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and 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.

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