Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans
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 (DHRS3), which...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Genetics in Medicine Open |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774425014669 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849694974185046016 |
|---|---|
| author | Akiko Soneda Hashimoto Jianshi Yu Christina Williams Karin Gaudenz Parisa Varshosaz Ruonan Zhao Nageswara Pilli Tian Liu Jonathon Russell Rebecca S. Tooze Stephen R.F. Twigg Siddharth Banka Elizabeth Sweeney Simon J. McGowan Samantha J.L. Knight Jenny C. Taylor Tawfiq Jamal Froukh M. Irene Valenzuela Palafoll Núria Martínez-Gil Mar Costa-Roger Maria Teresa Villarreal-Molina Esther Lieberman Hernandez Rami Abou Jamra Felix Gattermann Margarete Koch-Hogrebe Dagmar Wieczorek Paul A. Trainor Alexander R. Moise Andrew O.M. Wilkie Maureen A. Kane |
| author_facet | Akiko Soneda Hashimoto Jianshi Yu Christina Williams Karin Gaudenz Parisa Varshosaz Ruonan Zhao Nageswara Pilli Tian Liu Jonathon Russell Rebecca S. Tooze Stephen R.F. Twigg Siddharth Banka Elizabeth Sweeney Simon J. McGowan Samantha J.L. Knight Jenny C. Taylor Tawfiq Jamal Froukh M. Irene Valenzuela Palafoll Núria Martínez-Gil Mar Costa-Roger Maria Teresa Villarreal-Molina Esther Lieberman Hernandez Rami Abou Jamra Felix Gattermann Margarete Koch-Hogrebe Dagmar Wieczorek Paul A. Trainor Alexander R. Moise Andrew O.M. Wilkie Maureen A. Kane |
| author_sort | Akiko Soneda Hashimoto |
| collection | DOAJ |
| description | 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 (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. 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 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. Conclusion: 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. |
| format | Article |
| id | doaj-art-658d48e32fea4a55a4d033bfc31437f7 |
| institution | DOAJ |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj-art-658d48e32fea4a55a4d033bfc31437f72025-08-20T03:19:54ZengElsevierGenetics in Medicine Open2949-77442025-01-01310342710.1016/j.gimo.2025.103427Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humansAkiko Soneda Hashimoto0Jianshi Yu1Christina Williams2Karin Gaudenz3Parisa Varshosaz4Ruonan Zhao5Nageswara Pilli6Tian Liu7Jonathon Russell8Rebecca S. Tooze9Stephen R.F. Twigg10Siddharth Banka11Elizabeth Sweeney12Simon J. McGowan13Samantha J.L. Knight14Jenny C. Taylor15Tawfiq Jamal Froukh16M. Irene Valenzuela Palafoll17Núria Martínez-Gil18Mar Costa-Roger19Maria Teresa Villarreal-Molina20Esther Lieberman Hernandez21Rami Abou Jamra22Felix Gattermann23Margarete Koch-Hogrebe24Dagmar Wieczorek25Paul A. Trainor26Alexander R. Moise27Andrew O.M. Wilkie28Maureen A. Kane29Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MDDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MDStowers Institute for Medical Research, Kansas City, MOMedical Sciences Division, Northern Ontario School of Medicine University, Sudbury, ON, CanadaStowers Institute for Medical Research, Kansas City, MODepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MDDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MDStowers Institute for Medical Research, Kansas City, MOClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United KingdomDepartment of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, United KingdomCentre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomOxford NIHR Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, United KingdomOxford NIHR Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, United KingdomDepartment of Biotechnology and Genetic Engineering, Philadelphia University, Amman, JordanDepartment of Clinical and Molecular Genetics, Vall d´Hebron University Hospital, Barcelona, Spain; Medicine Genetics Group, Vall d’Hebron Research Institute, Barcelona, SpainDepartment of Clinical and Molecular Genetics, Vall d´Hebron University Hospital, Barcelona, Spain; Medicine Genetics Group, Vall d’Hebron Research Institute, Barcelona, SpainDepartment of Clinical and Molecular Genetics, Vall d´Hebron University Hospital, Barcelona, Spain; Medicine Genetics Group, Vall d’Hebron Research Institute, Barcelona, SpainLaboratorio de Genómica Cardiovascular, Instituto Nacional de Medicina Genómica, Mexico City, MexicoDepartamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City, MexicoInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, GermanyInstitute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyVestische Kinder und Jugendklinik Datteln, Universität Witten-Herdecke, Datteln, GermanyInstitute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyStowers Institute for Medical Research, Kansas City, MO; University of Kansas Medical Center, Department of Anatomy and Cell Biology, Kansas City, KSMedical Sciences Division, Northern Ontario School of Medicine University, Sudbury, ON, CanadaClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Correspondence and requests for materials should be addressed to Andrew O.M. Wilkie, Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD; Maureen A. Kane, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Pharmacy Hall North, Room 731, 20 N. Pine Street, Baltimore, MD 21201.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 (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. 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 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. Conclusion: 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.http://www.sciencedirect.com/science/article/pii/S29497744250146695′-untranslated regionCraniosynostosisNoncoding variantRetinoic acidVitamin A |
| spellingShingle | Akiko Soneda Hashimoto Jianshi Yu Christina Williams Karin Gaudenz Parisa Varshosaz Ruonan Zhao Nageswara Pilli Tian Liu Jonathon Russell Rebecca S. Tooze Stephen R.F. Twigg Siddharth Banka Elizabeth Sweeney Simon J. McGowan Samantha J.L. Knight Jenny C. Taylor Tawfiq Jamal Froukh M. Irene Valenzuela Palafoll Núria Martínez-Gil Mar Costa-Roger Maria Teresa Villarreal-Molina Esther Lieberman Hernandez Rami Abou Jamra Felix Gattermann Margarete Koch-Hogrebe Dagmar Wieczorek Paul A. Trainor Alexander R. Moise Andrew O.M. Wilkie Maureen A. Kane Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans Genetics in Medicine Open 5′-untranslated region Craniosynostosis Noncoding variant Retinoic acid Vitamin A |
| title | Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans |
| title_full | Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans |
| title_fullStr | Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans |
| title_full_unstemmed | Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans |
| title_short | Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans |
| title_sort | identification and characterization of short chain dehydrogenase reductase 3 dhrs3 deficiency a retinoic acid embryopathy of humans |
| topic | 5′-untranslated region Craniosynostosis Noncoding variant Retinoic acid Vitamin A |
| url | http://www.sciencedirect.com/science/article/pii/S2949774425014669 |
| work_keys_str_mv | AT akikosonedahashimoto identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT jianshiyu identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT christinawilliams identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT karingaudenz identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT parisavarshosaz identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT ruonanzhao identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT nageswarapilli identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT tianliu identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT jonathonrussell identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT rebeccastooze identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT stephenrftwigg identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT siddharthbanka identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT elizabethsweeney identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT simonjmcgowan identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT samanthajlknight identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT jennyctaylor identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT tawfiqjamalfroukh identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT mirenevalenzuelapalafoll identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT nuriamartinezgil identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT marcostaroger identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT mariateresavillarrealmolina identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT estherliebermanhernandez identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT ramiaboujamra identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT felixgattermann identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT margaretekochhogrebe identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT dagmarwieczorek identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT paulatrainor identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT alexanderrmoise identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT andrewomwilkie identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans AT maureenakane identificationandcharacterizationofshortchaindehydrogenasereductase3dhrs3deficiencyaretinoicacidembryopathyofhumans |