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

Pamela Magini; Daphne J Smits; Laura Vandervore; Rachel Schot; Marta Columbaro; Esmee Kasteleijn; Mees van der Ent; Flavia Palombo; Maarten H Lequin; Marjolein Dremmen; Marie Claire Y de Wit; Mariasavina Severino; Maria Teresa Divizia; Pasquale Striano; Natalia Ordonez-Herrera; Amal Alhashem; Ahmed Al Fares; Malak Al Ghamdi; Arndt Rolfs; Peter Bauer; Jeroen Demmers; Frans W Verheijen; Martina Wilke; Marjon van Slegtenhorst; Peter J van der Spek; Marco Seri; Anna C Jansen; Rolf W Stottmann; Robert B Hufnagel; Robert J Hopkin; Deema Aljeaid; Wojciech Wiszniewski; Pawel Gawlinski; Milena Laure-Kamionowska; Fowzan S Alkuraya; Hanah Akleh; Valentina Stanley; Damir Musaev; Joseph G Gleeson; Maha S Zaki; Nicola Brunetti-Pierri; Gerarda Cappuccio; Bella Davidov; Lina Basel-Salmon; Lily Bazak; Noa Ruhrman Shahar; Aida Bertoli-Avella; Ghayda M Mirzaa; William B Dobyns; Tommaso Pippucci; Maarten Fornerod; Grazia M S Mancini

doi:10.1016/j.ajhg.2019.08.006

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

Am J Hum Genet. 2019 Oct 3;105(4):689-705. doi: 10.1016/j.ajhg.2019.08.006. Epub 2019 Sep 5.

Authors

Pamela Magini¹, Daphne J Smits², Laura Vandervore³, Rachel Schot², Marta Columbaro⁴, Esmee Kasteleijn², Mees van der Ent⁵, Flavia Palombo⁶, Maarten H Lequin⁷, Marjolein Dremmen⁸, Marie Claire Y de Wit⁹, Mariasavina Severino¹⁰, Maria Teresa Divizia¹¹, Pasquale Striano¹², Natalia Ordonez-Herrera¹³, Amal Alhashem¹⁴, Ahmed Al Fares¹⁴, Malak Al Ghamdi¹⁵, Arndt Rolfs¹³, Peter Bauer¹³, Jeroen Demmers¹⁶, Frans W Verheijen², Martina Wilke², Marjon van Slegtenhorst², Peter J van der Spek¹⁷, Marco Seri¹⁸, Anna C Jansen¹⁹, Rolf W Stottmann²⁰, Robert B Hufnagel²¹, Robert J Hopkin²², Deema Aljeaid²³, Wojciech Wiszniewski²⁴, Pawel Gawlinski²⁵, Milena Laure-Kamionowska²⁶, Fowzan S Alkuraya²⁷, Hanah Akleh²⁸, Valentina Stanley²⁹, Damir Musaev²⁹, Joseph G Gleeson²⁹, Maha S Zaki³⁰, Nicola Brunetti-Pierri³¹, Gerarda Cappuccio³¹, Bella Davidov³², Lina Basel-Salmon³³, Lily Bazak³², Noa Ruhrman Shahar³², Aida Bertoli-Avella¹³, Ghayda M Mirzaa³⁴, William B Dobyns³⁵, Tommaso Pippucci³⁶, Maarten Fornerod⁵, Grazia M S Mancini³⁷

Affiliations

¹ Medical Genetics Unit, S.Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy.
² Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
³ 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.
⁴ Laboratory of Musculoskeletal Cell Biology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
⁵ Department of Cell Biology, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
⁶ IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy.
⁷ Department of Radiology, University medical center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
⁸ Department of Radiology, Sophia Children's hospital, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
⁹ Department of Child Neurology, Sophia Children's hospital, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
¹⁰ Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
¹¹ UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
¹² 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.
¹³ CENTOGENE AG. Am Strande 7, 18055 Rostock, Germany.
¹⁴ Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 12233, Saudi Arabia; Department of Pediatrics, College of Medicine, Qassim University, Qassim 52571, Saudi Arabia.
¹⁵ Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
¹⁶ Proteomics Center, Room Ee-679A, Erasmus University Medical Center. Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
¹⁷ Department of Pathology, Clinical Bioinformatics, ErasmusMC University Medical Center PO Box, 3000CA Rotterdam, the Netherlands.
¹⁸ Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, 40138 Bologna, Italy.
¹⁹ Vrije Universiteit Brussel, Centrum Medische Genetica, Laarbeeklaan 101, 1090 Brussels, Belgium; Pediatric Neurology Unit, UZ Univeristy of Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
²⁰ Department of Human Genetics, Division of Developmental Biology Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA.
²¹ Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 10N109, Bethesda, MD 20892, USA.
²² 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.
²³ Department of Human Genetics, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
²⁴ 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.
²⁵ Institute of Mother and Child, Kasprzaka 17a, 02-211 Warsaw, Poland.
²⁶ Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
²⁷ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
²⁸ Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
²⁹ Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA 92093, USA.
³⁰ Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo 12622, Egypt.
³¹ Department of Translational Medicine, University of Naples "Federico II," Naples 80131, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.
³² Department of Medical Genetics, Recanati Genetic Institute Rabin Medical Center, Beilinson Campus, Petah Tikva, 49100 Tel Aviv, Israel.
³³ 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.
³⁴ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
³⁵ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
³⁶ Medical Genetics Unit, S.Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy. Electronic address: tommaso.pippucci@gmail.com.
³⁷ Department of Clinical Genetics, ErasmusMC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Electronic address: g.mancini@erasmusmc.nl.

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.

Keywords: NET13; SMPD4; arthrogryposis; microcephaly; neutral-sphingomyelinase.

Publication types

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

MeSH terms

Arthrogryposis / genetics*
Arthrogryposis / pathology
Cell Lineage
Child
Endoplasmic Reticulum / metabolism
Female
Gene Expression Profiling
HEK293 Cells
Humans
Male
Microcephaly / genetics*
Microcephaly / pathology
Mitosis
Neurodevelopmental Disorders / genetics*
Neurodevelopmental Disorders / pathology
Pedigree
RNA Splicing
Sphingomyelin Phosphodiesterase / genetics*

Substances

SMPD3 protein, human
Sphingomyelin Phosphodiesterase

Abstract

Publication types

MeSH terms

Substances

Grants and funding