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

Brain. 2017 Feb;140(2):370-386. doi: 10.1093/brain/aww295.

Tzipora C Falik Zaccai ¹ ², David Savitzki ³, Yifat Zivony-Elboum ⁴, Thierry Vilboux ⁵ ⁶, Eric C Fitts ⁷, Yishay Shoval ⁴, Limor Kalfon ⁴, Nadra Samra ⁴, Zohar Keren ⁴, Bella Gross ² ⁸, Natalia Chasnyk ⁴, Rachel Straussberg ⁹ ¹⁰, James C Mullikin ¹¹ ¹², Jamie K Teer ¹³, Dan Geiger ¹⁴, Daniel Kornitzer ¹⁵, Ora Bitterman-Deutsch ² ¹⁶, Abraham O Samson ², Maki Wakamiya ¹⁷, Johnny W Peterson ⁷, Michelle L Kirtley ⁷, Iryna V Pinchuk ¹⁸, Wallace B Baze ¹⁹, William A Gahl ⁵, Robert Kleta ²⁰, Yair Anikster ¹⁰ ²¹, Ashok K Chopra ⁷

Affiliations

1 Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel falikmd.genetics@gmail.com.
2 Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel.
3 Pediatric Neurology Unit, Galilee Medical Center, Nahariya, Israel.
4 Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
5 Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
6 Division of Medical Genomics, Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
7 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
8 Department of Neurology, Galilee Medical Center, Nahariya, Israel.
9 Pediatric Neurology Unit, Schneider Children's Medical Center, Petach Tikva, Israel.
10 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
11 Comparative Genomics Analysis Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
12 NIH Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD, USA.
13 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
14 Computer Sciences, Technion - Israel Institute of Technology, Haifa, Israel.
15 Faculty of Medicine, Technion - I.I.T. and Rappaport Institute for Biomedical Research, Haifa, Israel.
16 Dermatology Clinic, Galilee Medical Center, Nahariya, Israel.
17 Transgenic Mouse Core Facility, Institute for Translational Sciences and Animal Resource Center, University of Texas Medical Branch, Galveston, TX, USA.
18 Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
19 Department of Veterinary Sciences, MD Anderson Cancer Center, Bastrop, TX, USA.
20 University College, Royal Free Hospital / UCL Medical School, London, UK.
21 Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Aviv, Israel.

PMID: 28007986 DOI: 10.1093/brain/aww295

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 A2-activating protein (PLAA); progressive leukoencephalopathy; startle response.

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