A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome

作者：Alakbarzade Vafa; Hameed Abdul; Quek Debra Q Y; Chioza Barry A; Baple Emma L; Cazenave Gassiot Amaury; Nguyen Long N; Wenk Markus R; Ahmad Arshia Q; Sreekantan Nair Ajith; Weedon Michael N; Rich Phil; Patton Michael A; Warner Thomas T; Silver David L; Cro**y Andrew H^*

来源：Nature Genetics, 2015, 47(7): 814-+.

DOI：10.1038/ng.3313

The major pathway by which the brain obtains essential omega-3 fatty acids from the circulation is through a sodium-dependent lysophosphatidylcholine (LPC) transporter (MFSD2A), expressed in the endothelium of the blood-brain barrier. Here we show that a homozygous mutation affecting a highly conserved MFSD2A residue (p.Ser339Leu) is associated with a progressive microcephaly syndrome characterized by intellectual disability, spasticity and absent speech. We show that the p.Ser339Leu alteration does not affect protein or cell surface expression but rather significantly reduces, although not completely abolishes, transporter activity. Notably, affected individuals displayed significantly increased plasma concentrations of LPCs containing mono-and polyunsaturated fatty acyl chains, indicative of reduced brain uptake, confirming the specificity of MFSD2A for LPCs having mono- and polyunsaturated fatty acyl chains. Together, these findings indicate an essential role for LPCs in human brain development and function and provide the first description of disease associated with aberrant brain LPC transport in humans.

• 出版日期2015-7