ArticleAmerican journal of human genetics2019
Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
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Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed, 83 citations in OpenAlex.
- Disulfidptosis-related genes and long non-coding RNAs define a prognostic model for liver cancer.Translational cancer research · 2026Article
- Reprogramming lipid metabolism in virus-infected neuronal cells.Research square · 2026Article
- Global profiling of protein lactylation in pancreatic ductal adenocarcinoma.Scientific reports · 2026Article
- Functional profiling and visualization of the sphingolipid metabolic network in vivo.EMBO reports · 2025Article
- Toxicological mechanisms of carbon polymers in accelerating cognitive decline in Alzheimer's disease.Journal of advanced research · 2025Article
- Clinical utility of DNA-methylation signatures in routine diagnostics for neurodevelopmental disorders.European journal of human genetics : EJHG · 2025Article
- Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia.Neurobiology of disease · 2025Article
- A whole-genome scan for evidence of positive and balancing selection in aye-ayes (Daubentonia madagascariensis) utilizing a well-fit evolutionary baseline model.G3 (Bethesda, Md.) · 2025Article
- Effects of heterozygous SMG1 mutations on nonsense-mediated mRNA decay in human pluripotent stem cell model.Molecules and cells · 2025Article
- Genomic exploration of pediatric neurological disorders: a case series.Journal of medical case reports · 2025Article
- A lineage-specific protein network at the trypanosome nuclear envelope.Nucleus (Austin, Tex.) · 2024Article
- SMPD4-mediated sphingolipid metabolism regulates brain and primary cilia development.Development (Cambridge, England) · 2024Article
- A whole-genome scan for evidence of recent positive and balancing selection in aye-ayes (bioRxiv : the preprint server for biology · 2024Article
- Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.bioRxiv : the preprint server for biology · 2024Article
- Ying and Yang of Ceramide in the Vascular Endothelium.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
- Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.Neurogenetics · 2024Review
- Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome.American journal of human genetics · 2023Article
- Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.Research square · 2023Article
- Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases.BMC medical genomics · 2023Article
- SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.Brain : a journal of neurology · 2023Article
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Authors and funding
52 authors at 20 institutions in 9 countries.
Pamela MaginiMedical Genetics Unit, S.Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy.
Daphne J SmitsDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Laura VandervoreDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; Vrije Universiteit Brussel, Centrum Medische Genetica, Laarbeeklaan 101, 1090 Brussels, Belgium.
Rachel SchotDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Marta ColumbaroLaboratory of Musculoskeletal Cell Biology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
Esmee KasteleijnDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Mees van der EntDepartment of Cell Biology, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Flavia PalomboIRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy.
Maarten H LequinDepartment of Radiology, University medical center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Marjolein DremmenDepartment of Radiology, Sophia Children's hospital, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Marie Claire Y de WitDepartment of Child Neurology, Sophia Children's hospital, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Mariasavina SeverinoNeuroradiology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
Maria Teresa DiviziaUOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
Pasquale StrianoPediatric Neurology and Muscular diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; Department of neursciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, 16126 Genova, Italy.
Natalia Ordonez-HerreraCENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.
Amal AlhashemDepartment of Pediatrics, Prince Sultan Military Medical City, Riyadh 12233, Saudi Arabia; Department of Pediatrics, College of Medicine, Qassim University, Qassim 52571, Saudi Arabia.
Ahmed Al FaresDepartment of Pediatrics, Prince Sultan Military Medical City, Riyadh 12233, Saudi Arabia; Department of Pediatrics, College of Medicine, Qassim University, Qassim 52571, Saudi Arabia.
Malak Al GhamdiDepartment of Pediatrics, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
Arndt RolfsCENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.
Peter BauerCENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.
Jeroen DemmersProteomics Center, Room Ee-679A, Erasmus University Medical Center. Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
Frans W VerheijenDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Martina WilkeDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Marjon van SlegtenhorstDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Peter J van der SpekDepartment of Pathology, Clinical Bioinformatics, ErasmusMC University Medical Center PO Box, 3000CA Rotterdam, the Netherlands.
Marco SeriMedical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy.
Anna C JansenVrije Universiteit Brussel, Centrum Medische Genetica, Laarbeeklaan 101, 1090 Brussels, Belgium; Pediatric Neurology Unit, UZ Univeristy of Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
Rolf W StottmannDepartment of Human Genetics, Division of Developmental Biology Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA.
Robert B HufnagelMedical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 10N109, Bethesda, MD 20892, USA.
Robert J HopkinDepartment of Human Genetics, Division of Developmental Biology Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, 3333 Burnet Ave., ML 4006, Cincinnati, OH 45229, USA.
Deema AljeaidDepartment of Human Genetics, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Wojciech WiszniewskiOregon Health & Sciences University, 3181 SW Sam Jackson Park Road L103, Portland, OR, USA; Institute of Mother and Child, Kasprzaka 17a, 02-211 Warsaw, Poland.
Pawel GawlinskiInstitute of Mother and Child, Kasprzaka 17a, 02-211 Warsaw, Poland.
Milena Laure-KamionowskaDepartment of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
Fowzan S AlkurayaDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hanah AklehDepartment of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
Valentina StanleyLaboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.
Damir MusaevLaboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.
Joseph G GleesonLaboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.
Maha S ZakiHuman Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo 12622, Egypt.
Nicola Brunetti-PierriDepartment of Translational Medicine, University of Naples "Federico II," Naples 80131, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.
Gerarda CappuccioDepartment of Translational Medicine, University of Naples "Federico II," Naples 80131, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.
Bella DavidovDepartment of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.
Lina Basel-SalmonDepartment of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Lily BazakDepartment of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.
Noa Ruhrman ShaharDepartment of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.
Aida Bertoli-AvellaCENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.
Ghayda M MirzaaDepartment of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
William B DobynsDepartment of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Tommaso PippucciMedical Genetics Unit, S.Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy. Electronic address: tommaso.pippucci@gmail.com.
Maarten FornerodDepartment of Cell Biology, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Grazia M S ManciniDepartment of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Electronic address: g.mancini@erasmusmc.nl.
Erasmus MC · NLCentogene (Germany) · DERabin Medical Center · ILCincinnati Children's Hospital Medical Center · USHoward Hughes Medical Institute · USIstituti di Ricovero e Cura a Carattere Scientifico · ITIstituto Giannina Gaslini · ITKing Faisal Specialist Hospital & Research Centre · SAPoliclinico S.Orsola-Malpighi · ITQassim University · SAUniversity of Naples Federico II · ITUniversity of Washington · USVrije Universiteit Brussel · BEIstituto Ortopedico Rizzoli · ITKing Abdulaziz University · SAKing Saud University · SANational Institutes of Health · USNational Research Centre · EGOregon Health & Science University · USPolish Academy of Sciences · PL
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MGenomic and epigenomic mechanisms of pediatric ocular disordersZIAEY000565 · NEI · NATIONAL EYE INSTITUTE · PI HUFNAGEL, ROBERT · 2019 to 2024
$11.4MThe Genetic Basis of Mid-Hindbrain MalformationsR01NS050375 · NINDS · UNIVERSITY OF MINNESOTA · PI DOBYNS, WILLIAM B. · 2005 to 2019
$9.9MForward Genetic Analysis of Congenital Defects in Cortical Circuits and StructureR01NS085023 · NINDS · CINCINNATI CHILDRENS HOSP MED CTR · PI STOTTMANN, ROLF W · 2014 to 2018
$2.3MGenes and pathways underlying brain overgrowth and focal cortical malformationsK08NS092898 · NINDS · SEATTLE CHILDREN'S HOSPITAL · PI MIRZAA, GHAYDA · 2015 to 2019
$930kNHGRI NIH HHS U54 HG003067NHGRI NIH HHS UM1 HG008900NINDS NIH HHS K08 NS092898NINDS NIH HHS R01 NS050375NINDS NIH HHS R01 NS085023
Abstract
Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.
Indexed as
ArthrogryposisCell LineageChildEndoplasmic ReticulumFemaleGene Expression ProfilingHEK293 CellsHumansMaleMicrocephalyMitosisNeurodevelopmental DisordersPedigreeRNA SplicingSphingomyelin PhosphodiesteraseSMPD3 protein, humanSphingomyelin PhosphodiesterasearthrogryposismicrocephalyNET13neutral-sphingomyelinaseSMPD4
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