Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.
Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.
1] Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK. [2] Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
Sérgio B
SB
Sousa
1] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2].
Dagan
D
Jenkins
1] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London, UK. [2].
Estelle
E
Chanudet
1] Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. [2].
Guergana
G
Tasseva
Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK.
Miho
M
Ishida
Histopathology Department, Great Ormond Street Hospital for Children, London, UK.
Glenn
G
Anderson
Neural Development Unit, UCL Institute of Child Health, London, UK.
James
J
Docker
1] Reta Lila Weston Institute, UCL Institute of Neurology, London, UK. [2] Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Mina
M
Ryten
Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
Joaquim
J
Sa
1] Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. [2] University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Jorge M
JM
Saraiva
Clinical Genetics Department, Great Ormond Street Hospital, London, UK.
Angela
A
Barnicoat
Clinical Genetics Department, Great Ormond Street Hospital, London, UK.
Richard
R
Scott
Radiology Department, Great Ormond Street Hospital, London, UK.
Alistair
A
Calder
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Duangrurdee
D
Wattanasirichaigoon
Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
Krystyna
K
Chrzanowska
Department of Biology and Medical Genetics, University Hospital Motol and Second Faculty of Medicine, Prague, Czech Republic.
Martina
M
Simandlová
1] Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France. [2] Cutis Laxa Study Group, University of Franche-Comté, Besancon, France.
Lionel
L
Van Maldergem
Neural Development Unit, UCL Institute of Child Health, London, UK.
Philip
P
Stanier
1] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London, UK.
Philip L
PL
Beales
Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Jean E
JE
Vance
Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK.
Gudrun E
GE
Moore
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D004392:Dwarfism; D004625:Embryo, Nonmammalian; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015576:Hyperostosis; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019884:Nitrogenous Group Transferases / Q000235:genetics* / Q000378:metabolism; D010718:Phosphatidylserines / Q000096:biosynthesis / Q000235:genetics; D013577:Syndrome; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D010718:Phosphatidylserines; D019884:Nitrogenous Group Transferases; C022370:phospholipid serine base exchange enzyme