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Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. / Magini, Pamela; Smits, Daphne J; Vandervore, Laura; Schot, Rachel; Columbaro, Marta; Kasteleijn, Esmee; van der Ent, Mees; Palombo, Flavia; Lequin, Maarten H; Dremmen, Marjolein; de Wit, Marie Claire Y; Severino, Mariasavina; Divizia, Maria Teresa; Striano, Pasquale; Ordonez-Herrera, Natalia; Alhashem, Amal; Al Fares, Ahmed; Al Ghamdi, Malak; Rolfs, Arndt; Bauer, Peter; Demmers, Jeroen; Verheijen, Frans W; Wilke, Martina; van Slegtenhorst, Marjon; van der Spek, Peter J; Seri, Marco; Jansen, Anna C; Stottmann, Rolf W; Hufnagel, Robert B; Hopkin, Robert J; Aljeaid, Deema; Wiszniewski, Wojciech; Gawlinski, Pawel; Laure-Kamionowska, Milena; Alkuraya, Fowzan S; Akleh, Hanah; Stanley, Valentina; Musaev, Damir; Gleeson, Joseph G; Zaki, Maha S; Brunetti-Pierri, Nicola; Cappuccio, Gerarda; Davidov, Bella; Basel-Salmon, Lina; Bazak, Lily; Shahar, Noa Ruhrman; Bertoli-Avella, Aida; Mirzaa, Ghayda M; Dobyns, William B; Pippucci, Tommaso; Fornerod, Maarten; Mancini, Grazia M S.

In: American Journal of Human Genetics, Vol. 105, No. 4, 03.10.2019, p. 689-705.

Research output: Contribution to journalArticle

Harvard

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

APA

Magini, P., Smits, D. J., Vandervore, L., Schot, R., Columbaro, M., Kasteleijn, E., ... 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

Vancouver

Magini P, Smits DJ, Vandervore L, Schot R, Columbaro M, Kasteleijn E et al. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. American Journal of Human Genetics. 2019 Oct 3;105(4):689-705. https://doi.org/10.1016/j.ajhg.2019.08.006

Author

Magini, Pamela ; Smits, Daphne J ; Vandervore, Laura ; Schot, Rachel ; Columbaro, Marta ; Kasteleijn, Esmee ; van der Ent, Mees ; Palombo, Flavia ; Lequin, Maarten H ; Dremmen, Marjolein ; de Wit, Marie Claire Y ; Severino, Mariasavina ; Divizia, Maria Teresa ; Striano, Pasquale ; Ordonez-Herrera, Natalia ; Alhashem, Amal ; Al Fares, Ahmed ; Al Ghamdi, Malak ; Rolfs, Arndt ; Bauer, Peter ; Demmers, Jeroen ; Verheijen, Frans W ; Wilke, Martina ; van Slegtenhorst, Marjon ; van der Spek, Peter J ; Seri, Marco ; Jansen, Anna C ; Stottmann, Rolf W ; Hufnagel, Robert B ; Hopkin, Robert J ; Aljeaid, Deema ; Wiszniewski, Wojciech ; Gawlinski, Pawel ; Laure-Kamionowska, Milena ; Alkuraya, Fowzan S ; Akleh, Hanah ; Stanley, Valentina ; Musaev, Damir ; Gleeson, Joseph G ; Zaki, Maha S ; Brunetti-Pierri, Nicola ; Cappuccio, Gerarda ; Davidov, Bella ; Basel-Salmon, Lina ; Bazak, Lily ; Shahar, Noa Ruhrman ; Bertoli-Avella, Aida ; Mirzaa, Ghayda M ; Dobyns, William B ; Pippucci, Tommaso ; Fornerod, Maarten ; Mancini, Grazia M S. / Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 4. pp. 689-705.

BibTeX

@article{bdcf34ec92534ca39a46e2b26157d99f,
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.",
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 = "Copyright {\circledC} 2019 American Society of Human Genetics. All rights reserved.",
year = "2019",
month = "10",
day = "3",
doi = "10.1016/j.ajhg.2019.08.006",
language = "English",
volume = "105",
pages = "689--705",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

RIS

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

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.

U2 - 10.1016/j.ajhg.2019.08.006

DO - 10.1016/j.ajhg.2019.08.006

M3 - Article

C2 - 31495489

VL - 105

SP - 689

EP - 705

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -

ID: 48242948