Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Arthrogryposis / genetics Cell Lineage Child Endoplasmic Reticulum / metabolism Female Gene Expression Profiling HEK293 Cells Humans Male Microcephaly / genetics Mitosis Neurodevelopmental Disorders / genetics Pedigree RNA Splicing Sphingomyelin Phosphodiesterase / genetics
NET13 SMPD4 arthrogryposis microcephaly neutral-sphingomyelinase

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
03 10 2019
Historique:
received: 07 05 2019
accepted: 15 08 2019
pubmed: 10 9 2019
medline: 3 4 2020
entrez: 10 9 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ajhg.2019.08.006 PMID: 31495489 PMC: PMC6817560
pubmed: 31495489
pii: S0002-9297(19)30309-X
doi: 10.1016/j.ajhg.2019.08.006
pmc: PMC6817560
pii:
doi:

Substances chimiques

SMPD3 protein, human EC 3.1.4.12
Sphingomyelin Phosphodiesterase EC 3.1.4.12

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

689-705

Subventions

Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003067
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS050375
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS085023
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS092898
Pays : United States

Informations de copyright

Copyright © 2019 American Society of Human Genetics. All rights reserved.

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Auteurs

Pamela Magini (P)

Medical Genetics Unit, S.Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy.

Daphne J Smits (DJ)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Laura Vandervore (L)

Department 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 Schot (R)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Marta Columbaro (M)

Laboratory of Musculoskeletal Cell Biology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

Esmee Kasteleijn (E)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Mees van der Ent (M)

Department of Cell Biology, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Flavia Palombo (F)

IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy.

Maarten H Lequin (MH)

Department of Radiology, University medical center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

Marjolein Dremmen (M)

Department of Radiology, Sophia Children's hospital, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Marie Claire Y de Wit (MCY)

Department of Child Neurology, Sophia Children's hospital, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Mariasavina Severino (M)

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.

Maria Teresa Divizia (MT)

UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.

Pasquale Striano (P)

Pediatric 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-Herrera (N)

CENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.

Amal Alhashem (A)

Department 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 Fares (A)

Department 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 Ghamdi (M)

Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.

Arndt Rolfs (A)

CENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.

Peter Bauer (P)

CENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.

Jeroen Demmers (J)

Proteomics Center, Room Ee-679A, Erasmus University Medical Center. Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.

Frans W Verheijen (FW)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Martina Wilke (M)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Marjon van Slegtenhorst (M)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Peter J van der Spek (PJ)

Department of Pathology, Clinical Bioinformatics, ErasmusMC University Medical Center PO Box, 3000CA Rotterdam, the Netherlands.

Marco Seri (M)

Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy.

Anna C Jansen (AC)

Vrije Universiteit Brussel, Centrum Medische Genetica, Laarbeeklaan 101, 1090 Brussels, Belgium; Pediatric Neurology Unit, UZ Univeristy of Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.

Rolf W Stottmann (RW)

Department of Human Genetics, Division of Developmental Biology Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA.

Robert B Hufnagel (RB)

Medical 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 Hopkin (RJ)

Department 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 Aljeaid (D)

Department of Human Genetics, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Wojciech Wiszniewski (W)

Oregon 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 Gawlinski (P)

Institute of Mother and Child, Kasprzaka 17a, 02-211 Warsaw, Poland.

Milena Laure-Kamionowska (M)

Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.

Fowzan S Alkuraya (FS)

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Hanah Akleh (H)

Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.

Valentina Stanley (V)

Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.

Damir Musaev (D)

Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.

Joseph G Gleeson (JG)

Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.

Maha S Zaki (MS)

Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo 12622, Egypt.

Nicola Brunetti-Pierri (N)

Department of Translational Medicine, University of Naples "Federico II," Naples 80131, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.

Gerarda Cappuccio (G)

Department of Translational Medicine, University of Naples "Federico II," Naples 80131, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.

Bella Davidov (B)

Department of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.

Lina Basel-Salmon (L)

Department 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 Bazak (L)

Department of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.

Noa Ruhrman Shahar (NR)

Department of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.

Aida Bertoli-Avella (A)

CENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.

Ghayda M Mirzaa (GM)

Department 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 Dobyns (WB)

Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

Tommaso Pippucci (T)

Medical Genetics Unit, S.Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy. Electronic address: tommaso.pippucci@gmail.com.

Maarten Fornerod (M)

Department of Cell Biology, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Grazia M S Mancini (GMS)

Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Electronic address: g.mancini@erasmusmc.nl.

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Classifications MeSH

questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations de l'appareil locomoteur › Arthrogrypose › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Reproduction › Développement embryonnaire et foetal › Développement embryonnaire › Lignage cellulaire › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Réticulum endoplasmique › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Malformations corticales › Malformations corticales du groupe I › Microcéphalie › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Phénomènes génétiques › Division du noyau cellulaire › Mitose › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Pedigree › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › Loss of SMPD4 Causes a Developmental Disorder...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Phosphodiesterases › Sphingomyeline phosphodiesterase › Loss of SMPD4 Causes a Developmental Disorder...