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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.

SUBMITTER: Magini P 

PROVIDER: S-EPMC6817560 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

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

American journal of human genetics 20190905 4

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 (nS  ...[more]

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