title: Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.
abstract: Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2and cytosolic phospholipase A2activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2and cytosolic phospholipase A2synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance.
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel falikmd.genetics@gmail.com.|Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel.
authors.forename: Tzipora C
authors.initials: TC
authors.lastname: Falik Zaccai
authors.affiliation: Pediatric Neurology Unit, Galilee Medical Center, Nahariya, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Savitzki
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Zivony-Elboum
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Division of Medical Genomics, Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Fitts
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Yishay
authors.initials: Y
authors.lastname: Shoval
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Kalfon
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Nadra
authors.initials: N
authors.lastname: Samra
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Keren
authors.affiliation: Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel.|Department of Neurology, Galilee Medical Center, Nahariya, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Gross
authors.affiliation: Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
authors.forename: Natalia
authors.initials: N
authors.lastname: Chasnyk
authors.affiliation: Pediatric Neurology Unit, Schneider Children's Medical Center, Petach Tikva, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.affiliation: Comparative Genomics Analysis Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|NIH Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.affiliation: Computer Sciences, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Geiger
authors.affiliation: Faculty of Medicine, Technion - I.I.T. and Rappaport Institute for Biomedical Research, Haifa, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kornitzer
authors.affiliation: Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel.|Dermatology Clinic, Galilee Medical Center, Nahariya, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Bitterman-Deutsch
authors.affiliation: Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel.
authors.forename: Abraham O
authors.initials: AO
authors.lastname: Samson
authors.affiliation: Transgenic Mouse Core Facility, Institute for Translational Sciences and Animal Resource Center, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Johnny W
authors.initials: JW
authors.lastname: Peterson
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Kirtley
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Iryna V
authors.initials: IV
authors.lastname: Pinchuk
authors.affiliation: Department of Veterinary Sciences, MD Anderson Cancer Center, Bastrop, TX, USA.
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Baze
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: University College, Royal Free Hospital / UCL Medical School, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Aviv, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chopra
mesh_terms: D000293:Adolescent; D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002648:Child; D003241:Consanguinity; D015232:Dinoprostone / Q000378:metabolism; D004622:Embryo, Mammalian; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012867:Skin / Q000473:pathology
chemical_list: D016328:NF-kappa B; D011506:Proteins; C055324:phospholipase A2-activating protein; D054467:Phospholipases A2; D015232:Dinoprostone
keywords: autosomal recessive; complex phospholipid defects; phospholipase A2-activating protein (PLAA); progressive leukoencephalopathy; startle response