Alicia Guemez-Gamboa 1, Long N Nguyen 2, Hongbo Yang 3, Maha S Zaki 4, Majdi Kara 5, Tawfeg Ben-Omran 6, Naiara Akizu 1, Rasim Ozgur Rosti 1, Basak Rosti 1, Eric Scott 1, Jana Schroth 1, Brett Copeland 1, Keith K Vaux 1, Amaury Cazenave-Gassiot 7, Debra Q Y Quek 2, Bernice H Wong 2, Bryan C Tan 2, Markus R Wenk 7, Murat Gunel 8, Stacey Gabriel 9, Neil C Chi 3, David L Silver 2, Joseph G Gleeson 1

1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
Department of Medicine, University of California, San Diego, La Jolla, California, USA
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Department of Biochemistry, National University of Singapore, Singapore.
Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology and Genetics, Yale University, School of Medicine, New Haven, Connecticut, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

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.

Keywords

Blood-brain barrier

Brain

DHA

EPA

Lysolipids

LPC

Major facilitator superfamily domain containing 2a (Mfsd2a)

Microcephaly

Nutrition