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

Nat Genet
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
7
Pages
809-13
Date Published
2015 Jul
ISSN
1546-1718
URL
DOI
10.1038/ng.3311
PubMed ID
26005868
PubMed Central ID
PMC4547531
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01NS048453 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54HG006504 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
Howard Hughes Medical Institute / United States
K99 NS089943 / NS / NINDS NIH HHS / United States
P01HD070494 / HD / NICHD NIH HHS / United States
K99NS089943 / NS / NINDS NIH HHS / United States