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

Abstract

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.

Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

“…1D). The two molecular weight species observed for Mfsd2a in the retina have been observed previously for Mfsd2a in liver and in overexpression studies in HEK293 cells and explained by alternative glycosylation (18,20). The single molecular weight species of Mfsd2a detected in RPE is similar to the molecular weight of Mfsd2a reported for brain (16).…”

“…Thus, the transport of plasma-derived LPCs might provide an abundant source of membrane building blocks for photoreceptor OS disc development. Indeed, the liver is the primary source for plasma LPC where LPC levels circulate on albumin in human and rodent plasma at high concentrations similar to concentrations of unesterified fatty acids (18,19,35). The specific reduction in OS length in Mfsd2a KO mice might be analogous to the microcephaly observed in mice and humans with Mfsd2a loss-of-function mutations, in which LPCs are required for brain growth (16,18,19).…”

“…In addition to DHA deficiency, Mfsd2a knock-out (KO) mice exhibit severe microcephaly and deficits in learning and memory. Importantly, we have identified humans with homozygous inactivating mutations in Mfsd2a that presented with severe microcephaly and intellectual impairments (18,19), indicating for the first time that plasma-derived LPCs are required for human brain growth and function. These findings raise the possibility that Mfsd2a is required for DHA uptake in eye.…”

“…Indeed, the liver is the primary source for plasma LPC where LPC levels circulate on albumin in human and rodent plasma at high concentrations similar to concentrations of unesterified fatty acids (18,19,35). The specific reduction in OS length in Mfsd2a KO mice might be analogous to the microcephaly observed in mice and humans with Mfsd2a loss-of-function mutations, in which LPCs are required for brain growth (16,18,19). Similar to the metabolic demands of the retina, neurons in the brain primarily consume glucose for production of ATP for the maintenance of cation pumps and membrane potential (36).…”

“…Lipidomic Analysis-Tissue lipid analysis was carried out as described previously (18). Wild-type and Mfsd2a KO mice aged 7-8 weeks or LL and LLTie2Cre mice aged 7 weeks were deeply anesthetized and perfused transcardially with 30 ml of saline.…”