Journal Article

Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome

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

2015

Overview

Joseph Gleeson, David Silver and colleagues show that inactivating mutations in MFSD2A , which encodes an essential transporter of long-chain fatty acids in brain, cause a lethal microcephaly syndrome. These results establish a link between the activity of this transporter and human brain growth. 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 1 , 2 . 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 3 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/51 / 14 / 631/208/1516 / 692/699/375/366 / 82 / Adolescent / Agriculture / Animal Genetics and Genomics / Animals / Biological Transport / Biomedicine / Blood-Brain Barrier - metabolism / Brain - metabolism / Brain research / Cancer Research / Case-Control Studies / Child / Child, Preschool / Consanguinity / Endothelium / Fatty acids / Fatty Acids, Omega-3 - metabolism / Female / Gene Function / Gene mutation / Genes, Lethal / Genetic aspects / Genetic Association Studies / Health aspects / HEK293 Cells / Human Genetics / Humans / Identification and classification / Infant / letter / Lipids / Male / Mice, Knockout / Microcephaly / Microcephaly - genetics / Microscopy / Mutation / Mutation, Missense / Omega 3 fatty acids / Proteins / Risk factors / Rodents / Studies / Syndrome / Tumor Suppressor Proteins - genetics / Zebrafish