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Nat Genet. 2015 Jul;47(7):814-7. doi: 10.1038/ng.3313. Epub 2015 May 25.

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

Author information

1
1] Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK. [2] Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neurosciences, University College London Institute of Neurology, London, UK.
2
Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
3
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
4
Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK.
5
1] Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK. [2] Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK. [3] Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
6
Life Sciences Institute, National University of Singapore, Singapore.
7
1] Department of Physical Medicine and Rehabilitation, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana, USA. [2] Rehabilitation Hospital Indiana, Indianapolis, Indiana, USA.
8
Department of Neuroradiology, St. George's Hospital, London, UK.
9
1] Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK. [2] Southwest Thames Regional Genetics Service, St George's Healthcare National Health Service (NHS) Trust, London, UK.
10
Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neurosciences, University College London Institute of Neurology, London, UK.

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.

PMID:
26005865
DOI:
10.1038/ng.3313
[Indexed for MEDLINE]

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