title: Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome.
abstract: Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Guemez-Gamboa
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Long N
authors.initials: LN
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yang
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
authors.forename: Majdi
authors.initials: M
authors.lastname: Kara
authors.affiliation: Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Naiara
authors.initials: N
authors.lastname: Akizu
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Rasim Ozgur
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Basak
authors.initials: B
authors.lastname: Rosti
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Copeland
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Vaux
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Amaury
authors.identifier: 000000023050634X
authors.initials: A
authors.lastname: Cazenave-Gassiot
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Debra Q Y
authors.initials: DQ
authors.lastname: Quek
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Bernice H
authors.initials: BH
authors.lastname: Wong
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology and Genetics, Yale University, School of Medicine, New Haven, Connecticut, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: David L
authors.initials: DL
authors.lastname: Silver
authors.affiliation: 1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000293:Adolescent; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005260:Female; D005804:Genes, Lethal; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics*; D020125:Mutation, Missense; D027981:Symporters; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015027:Zebrafish
chemical_list: D015525:Fatty Acids, Omega-3; C549328:MFSD2A protein, human; D027981:Symporters; D025521:Tumor Suppressor Proteins