人类视黄酸胚胎病——短链脱氢酶/还原酶3（DHRS3）缺乏症的鉴定与特征分析
Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans.
作者信息
Hashimoto Akiko Soneda, Yu Jianshi, Williams Christina, Gaudenz Karin, Varshosaz Parisa, Zhao Ruonan, Pilli Nageswara, Liu Tian, Russell Jonathon, Tooze Rebecca S, Twigg Stephen R F, Banka Siddharth, Sweeney Elizabeth, McGowan Simon J, Knight Samantha J L, Taylor Jenny C, Froukh Tawfiq Jamal, Palafoll M Irene Valenzuela, Martínez-Gil Núria, Costa-Roger Mar, Villarreal-Molina Maria Teresa, Lieberman Hernandez Esther, Abou Jamra Rami, Gattermann Felix, Koch-Hogrebe Margarete, Wieczorek Dagmar, Trainor Paul A, Moise Alexander R, Wilkie Andrew O M, Kane Maureen A
机构信息
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD.
出版信息
Genet Med Open. 2025 Mar 29;3:103427. doi: 10.1016/j.gimo.2025.103427. eCollection 2025.
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 8 sibships (12 individuals) segregating 5 different homozygous variants of dehydrogenase/reductase 3 ), 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.
METHODS
We assessed variant pathogenicity using comparative phenotypic and bioinformatic analysis, quantification of expression, and measurement of plasma retinoid metabolites.
RESULTS
Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of , 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 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.
CONCLUSION
We define a novel developmental syndrome associated with biallelic hypomorphic variants in ; a careful assessment of individual variants is required to establish a causal link to phenotype.
目的
形态发生素全反式维甲酸（RA）发出的信号对胚胎发育至关重要，在此过程中其组织浓度必须受到严格调控。我们研究了8个家系（12名个体），这些家系中分离出脱氢酶/还原酶3（DHRS3）的5种不同纯合变体，该基因编码一种胚胎期表达的酶（短链脱氢酶/还原酶3；也称为SDR16C1），可催化视黄醛还原为视黄醇，限制过量RA的合成。
方法
我们使用比较表型和生物信息学分析、DHRS3表达定量以及血浆类视黄醇代谢物测量来评估变体的致病性。
结果
来自3个家系的5名纯合子（1个家系分离出DHRS3启动子和5'非翻译区缺失，另外2个家系分离出错义变体p.(Val171Met)）表现出一致的表型，包括冠状颅缝早闭、面部畸形特征、先天性心脏病（4/5个体）和脊柱侧凸（5/5个体）。2名启动子/5'非翻译区缺失纯合子全血细胞中DHRS3的转录减少了90%至98%。与野生型相比，用DHRS3-Val171Met构建体转染的细胞表现出视黄醛还原能力降低，导致视黄醇减少和RA升高；相应地，与对照组和杂合子亲属相比，纯合患者的血浆视黄醇显著降低，RA升高（超过正常范围）。另外3种DHRS3纯合错义变体（p.(Val110Ile)、p.(Gly115Asp)和p.(Glu244Gln)）在体外和/或体内显示出催化活性降低，但与正常或不同的表型相关联，这些表型未达到判定可能致病性的阈值。
结论
我们定义了一种与DHRS3双等位基因低表达变体相关的新型发育综合征；需要对个体变体进行仔细评估以建立与表型的因果联系。
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