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 BauerJeroen 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

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)689-705
Number of pages17
JournalAmerican Journal of Human Genetics
Volume105
Issue number4
DOIs
StatePublished - 3 Oct 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 American Society of Human Genetics

Funding

We thank Mark Nellist, Niels Galjart, Danny Huylebroeck, Robert W. Hofstra, and Andreas Kremer for fruitful discussions and continuous support. G.M.S.M. is supported by ZonMW Top grant # 91217045 and by private donations. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898 and Jordan’s Guardian Angels (to G.M.M.). We thank the Broad Institute ( U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur). R.W.S. is supported by the NIH ( R01NS085023 ). We thank Lauren Blizzard with assistance in Sanger Sequence verification of affected individuals in family 8. We also thank Luisa Iommarini, Department of Pharmacy and Biotechnology-FABIT, University of Bologna, Bologna, Italy, for help with the LC3B western blots. W.W. was supported by a grant from National Science Centre, Poland 2015/19/B/NZ2/01824 . A.C.J. is supported by a fellowship from FWO . A.C.J., G.M.M., G.M.S.M., M.W., M.S.Z., and W.B.D. are members of the European Network on Brain malformations (COST Action CA16118, https://www.cost.eu/actions/CA16118/ ). We thank Mark Nellist, Niels Galjart, Danny Huylebroeck, Robert W. Hofstra, and Andreas Kremer for fruitful discussions and continuous support. G.M.S.M. is supported by ZonMW Top grant #91217045 and by private donations. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898 and Jordan's Guardian Angels (to G.M.M.). We thank the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur). R.W.S. is supported by the NIH (R01NS085023). We thank Lauren Blizzard with assistance in Sanger Sequence verification of affected individuals in family 8. We also thank Luisa Iommarini, Department of Pharmacy and Biotechnology-FABIT, University of Bologna, Bologna, Italy, for help with the LC3B western blots. W.W. was supported by a grant from National Science Centre, Poland 2015/19/B/NZ2/01824. A.C.J. is supported by a fellowship from FWO. A.C.J. G.M.M. G.M.S.M. M.W. M.S.Z. and W.B.D. are members of the European Network on Brain malformations (COST Action CA16118, https://www.cost.eu/actions/CA16118/).

FundersFunder number
Jordan's Guardian Angels
Jordan’s Guardian Angels
National Institutes of Health
National Institute of Neurological Disorders and StrokeK08NS092898, R01NS085023
Broad InstituteU54HG003067, UM1HG008900
ZonMw91217045
Fonds Wetenschappelijk OnderzoekCA16118
Narodowe Centrum Nauki2015/19/B/NZ2/01824
Università di Bologna

    Keywords

    • NET13
    • SMPD4
    • arthrogryposis
    • microcephaly
    • neutral-sphingomyelinase

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