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

• Published in: Nature genetics Vol. 47; no. 7; pp. 809 - 813
• Main Authors: Guemez-Gamboa, Alicia, Nguyen, Long N, Yang, Hongbo, Zaki, Maha S, Kara, Majdi, Ben-Omran, Tawfeg, Akizu, Naiara, Rosti, Rasim Ozgur, Rosti, Basak, Scott, Eric, Schroth, Jana, Copeland, Brett, Vaux, Keith K, Cazenave-Gassiot, Amaury, Quek, Debra Q Y, Wong, Bernice H, Tan, Bryan C, Wenk, Markus R, Gunel, Murat, Gabriel, Stacey, Chi, Neil C, Silver, David L, Gleeson, Joseph G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2015; Nature Publishing Group
• Subjects: 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
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3311

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.