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

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 journal › Article › peer-review

36 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 language	English (US)
Pages (from-to)	689-705
Number of pages	17
Journal	American Journal of Human Genetics
Volume	105
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2019.08.006
State	Published - Oct 3 2019
Externally published	Yes

Bibliographical note

Funding Information:
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/ ).

Funding Information:
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/).

Publisher Copyright:
© 2019 American Society of Human Genetics

Keywords

NET13
SMPD4
arthrogryposis
microcephaly
neutral-sphingomyelinase

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Magini, P., Smits, D. J., Vandervore, L., Schot, R., Columbaro, M., Kasteleijn, E., van der Ent, M., Palombo, F., Lequin, M. H., Dremmen, M., de Wit, M. C. Y., Severino, M., Divizia, M. T., Striano, P., Ordonez-Herrera, N., Alhashem, A., Al Fares, A., Al Ghamdi, M., Rolfs, A., ... Mancini, G. M. S. (2019). Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. American Journal of Human Genetics, 105(4), 689-705. https://doi.org/10.1016/j.ajhg.2019.08.006

Magini, P, Smits, DJ, Vandervore, L, Schot, R, Columbaro, M, Kasteleijn, E, van der Ent, M, Palombo, F, Lequin, MH, Dremmen, M, de Wit, MCY, Severino, M, Divizia, MT, Striano, P, Ordonez-Herrera, N, Alhashem, A, Al Fares, A, Al Ghamdi, M, Rolfs, A, Bauer, P, Demmers, J, Verheijen, FW, Wilke, M, van Slegtenhorst, M, van der Spek, PJ, Seri, M, Jansen, AC, Stottmann, RW, Hufnagel, RB, Hopkin, RJ, Aljeaid, D, Wiszniewski, W, Gawlinski, P, Laure-Kamionowska, M, Alkuraya, FS, Akleh, H, Stanley, V, Musaev, D, Gleeson, JG, Zaki, MS, Brunetti-Pierri, N, Cappuccio, G, Davidov, B, Basel-Salmon, L, Bazak, L, Shahar, NR, Bertoli-Avella, A, Mirzaa, GM, Dobyns, WB, Pippucci, T, Fornerod, M & Mancini, GMS 2019, 'Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis', American Journal of Human Genetics, vol. 105, no. 4, pp. 689-705. https://doi.org/10.1016/j.ajhg.2019.08.006

@article{97ea1e44c1b641c4947c161af4752b5a,

title = "Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis",

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",

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

note = "Funding Information: 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{\textquoteright}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/ ). Funding Information: 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/). Publisher Copyright: {\textcopyright} 2019 American Society of Human Genetics",

year = "2019",

month = oct,

day = "3",

doi = "10.1016/j.ajhg.2019.08.006",

language = "English (US)",

volume = "105",

pages = "689--705",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

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TY - JOUR

T1 - Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

AU - Magini, Pamela

AU - Smits, Daphne J.

AU - Vandervore, Laura

AU - Schot, Rachel

AU - Columbaro, Marta

AU - Kasteleijn, Esmee

AU - van der Ent, Mees

AU - Palombo, Flavia

AU - Lequin, Maarten H.

AU - Dremmen, Marjolein

AU - de Wit, Marie Claire Y.

AU - Severino, Mariasavina

AU - Divizia, Maria Teresa

AU - Striano, Pasquale

AU - Ordonez-Herrera, Natalia

AU - Alhashem, Amal

AU - Al Fares, Ahmed

AU - Al Ghamdi, Malak

AU - Rolfs, Arndt

AU - Bauer, Peter

AU - Demmers, Jeroen

AU - Verheijen, Frans W.

AU - Wilke, Martina

AU - van Slegtenhorst, Marjon

AU - van der Spek, Peter J.

AU - Seri, Marco

AU - Jansen, Anna C.

AU - Stottmann, Rolf W.

AU - Hufnagel, Robert B.

AU - Hopkin, Robert J.

AU - Aljeaid, Deema

AU - Wiszniewski, Wojciech

AU - Gawlinski, Pawel

AU - Laure-Kamionowska, Milena

AU - Alkuraya, Fowzan S.

AU - Akleh, Hanah

AU - Stanley, Valentina

AU - Musaev, Damir

AU - Gleeson, Joseph G.

AU - Zaki, Maha S.

AU - Brunetti-Pierri, Nicola

AU - Cappuccio, Gerarda

AU - Davidov, Bella

AU - Basel-Salmon, Lina

AU - Bazak, Lily

AU - Shahar, Noa Ruhrman

AU - Bertoli-Avella, Aida

AU - Mirzaa, Ghayda M.

AU - Dobyns, William B.

AU - Pippucci, Tommaso

AU - Fornerod, Maarten

AU - Mancini, Grazia M.S.

N1 - Funding Information: 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/ ). Funding Information: 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/). Publisher Copyright: © 2019 American Society of Human Genetics

PY - 2019/10/3

Y1 - 2019/10/3

N2 - 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.

AB - 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.

KW - NET13

KW - SMPD4

KW - arthrogryposis

KW - microcephaly

KW - neutral-sphingomyelinase

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

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