Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Tzipora C. Falik Zaccai, David Savitzki, Yifat Zivony-Elboum, Thierry Vilboux, Eric C. Fitts, Yishay Shoval, Limor Kalfon, Nadra Samra, Zohar Keren, Bella Gross, Natalia Chasnyk, Rachel Straussberg, James C. Mullikin, Jamie K. Teer, Dan Geiger, Daniel Kornitzer, Ora Bitterman-Deutsch, Abraham O. Samson, Maki Wakamiya, Johnny Peterson & 7 others Michelle L. Kirtley, Iryna Pinchuk, Wallace B. Baze, William A. Gahl, Robert Kleta, Yair Anikster, Ashok Chopra

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels 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 E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2. The 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.

Original languageEnglish (US)
Pages (from-to)370-386
Number of pages17
JournalBrain
Volume140
Issue number2
DOIs
StatePublished - 2017

Fingerprint

Leukoencephalopathies
Dinoprostone
Cytosolic Phospholipases A2
Fibroblasts
Maintenance
Phenotype
Microcephaly
Quadriplegia
Muscle Spasticity
Chromosome Mapping
Brain Diseases
Myelin Sheath
Computational Biology
Phenylalanine
Leucine
Phospholipids
Proteins
Central Nervous System
phospholipase A2-activating protein
Protein

Keywords

  • Autosomal recessive
  • Complex phospholipid defects
  • Phospholipase A-activating protein (PLAA)
  • Progressive leukoencephalopathy
  • Startle response

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Falik Zaccai, T. C., Savitzki, D., Zivony-Elboum, Y., Vilboux, T., Fitts, E. C., Shoval, Y., ... Chopra, A. (2017). Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. Brain, 140(2), 370-386. https://doi.org/10.1093/brain/aww295

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. / Falik Zaccai, Tzipora C.; Savitzki, David; Zivony-Elboum, Yifat; Vilboux, Thierry; Fitts, Eric C.; Shoval, Yishay; Kalfon, Limor; Samra, Nadra; Keren, Zohar; Gross, Bella; Chasnyk, Natalia; Straussberg, Rachel; Mullikin, James C.; Teer, Jamie K.; Geiger, Dan; Kornitzer, Daniel; Bitterman-Deutsch, Ora; Samson, Abraham O.; Wakamiya, Maki; Peterson, Johnny; Kirtley, Michelle L.; Pinchuk, Iryna; Baze, Wallace B.; Gahl, William A.; Kleta, Robert; Anikster, Yair; Chopra, Ashok.

In: Brain, Vol. 140, No. 2, 2017, p. 370-386.

Research output: Contribution to journalArticle

Falik Zaccai, TC, Savitzki, D, Zivony-Elboum, Y, Vilboux, T, Fitts, EC, Shoval, Y, Kalfon, L, Samra, N, Keren, Z, Gross, B, Chasnyk, N, Straussberg, R, Mullikin, JC, Teer, JK, Geiger, D, Kornitzer, D, Bitterman-Deutsch, O, Samson, AO, Wakamiya, M, Peterson, J, Kirtley, ML, Pinchuk, I, Baze, WB, Gahl, WA, Kleta, R, Anikster, Y & Chopra, A 2017, 'Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy', Brain, vol. 140, no. 2, pp. 370-386. https://doi.org/10.1093/brain/aww295
Falik Zaccai TC, Savitzki D, Zivony-Elboum Y, Vilboux T, Fitts EC, Shoval Y et al. Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. Brain. 2017;140(2):370-386. https://doi.org/10.1093/brain/aww295
Falik Zaccai, Tzipora C. ; Savitzki, David ; Zivony-Elboum, Yifat ; Vilboux, Thierry ; Fitts, Eric C. ; Shoval, Yishay ; Kalfon, Limor ; Samra, Nadra ; Keren, Zohar ; Gross, Bella ; Chasnyk, Natalia ; Straussberg, Rachel ; Mullikin, James C. ; Teer, Jamie K. ; Geiger, Dan ; Kornitzer, Daniel ; Bitterman-Deutsch, Ora ; Samson, Abraham O. ; Wakamiya, Maki ; Peterson, Johnny ; Kirtley, Michelle L. ; Pinchuk, Iryna ; Baze, Wallace B. ; Gahl, William A. ; Kleta, Robert ; Anikster, Yair ; Chopra, Ashok. / Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. In: Brain. 2017 ; Vol. 140, No. 2. pp. 370-386.
@article{a15a443980d14f75a3a5d4c55fe6e898,
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 E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels 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 E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2. The 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.",
keywords = "Autosomal recessive, Complex phospholipid defects, Phospholipase A-activating protein (PLAA), Progressive leukoencephalopathy, Startle response",
author = "{Falik Zaccai}, {Tzipora C.} and David Savitzki and Yifat Zivony-Elboum and Thierry Vilboux and Fitts, {Eric C.} and Yishay Shoval and Limor Kalfon and Nadra Samra and Zohar Keren and Bella Gross and Natalia Chasnyk and Rachel Straussberg and Mullikin, {James C.} and Teer, {Jamie K.} and Dan Geiger and Daniel Kornitzer and Ora Bitterman-Deutsch and Samson, {Abraham O.} and Maki Wakamiya and Johnny Peterson and Kirtley, {Michelle L.} and Iryna Pinchuk and Baze, {Wallace B.} and Gahl, {William A.} and Robert Kleta and Yair Anikster and Ashok Chopra",
year = "2017",
doi = "10.1093/brain/aww295",
language = "English (US)",
volume = "140",
pages = "370--386",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

AU - Falik Zaccai, Tzipora C.

AU - Savitzki, David

AU - Zivony-Elboum, Yifat

AU - Vilboux, Thierry

AU - Fitts, Eric C.

AU - Shoval, Yishay

AU - Kalfon, Limor

AU - Samra, Nadra

AU - Keren, Zohar

AU - Gross, Bella

AU - Chasnyk, Natalia

AU - Straussberg, Rachel

AU - Mullikin, James C.

AU - Teer, Jamie K.

AU - Geiger, Dan

AU - Kornitzer, Daniel

AU - Bitterman-Deutsch, Ora

AU - Samson, Abraham O.

AU - Wakamiya, Maki

AU - Peterson, Johnny

AU - Kirtley, Michelle L.

AU - Pinchuk, Iryna

AU - Baze, Wallace B.

AU - Gahl, William A.

AU - Kleta, Robert

AU - Anikster, Yair

AU - Chopra, Ashok

PY - 2017

Y1 - 2017

N2 - 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 E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels 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 E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2. The 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.

AB - 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 E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels 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 E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2. The 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.

KW - Autosomal recessive

KW - Complex phospholipid defects

KW - Phospholipase A-activating protein (PLAA)

KW - Progressive leukoencephalopathy

KW - Startle response

UR - http://www.scopus.com/inward/record.url?scp=85014782264&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014782264&partnerID=8YFLogxK

U2 - 10.1093/brain/aww295

DO - 10.1093/brain/aww295

M3 - Article

VL - 140

SP - 370

EP - 386

JO - Brain

JF - Brain

SN - 0006-8950

IS - 2

ER -