title: 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.
authors.affiliation: 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.
authors.forename: Vafa
authors.initials: V
authors.lastname: Alakbarzade
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Debra Q Y
authors.initials: DQ
authors.lastname: Quek
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK.
authors.forename: Barry A
authors.identifier: 0000000235461726
authors.initials: BA
authors.lastname: Chioza
authors.affiliation: 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.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baple
authors.affiliation: Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Amaury
authors.identifier: 000000023050634X
authors.initials: A
authors.lastname: Cazenave-Gassiot
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Long N
authors.initials: LN
authors.lastname: Nguyen
authors.affiliation: Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: 1] Department of Physical Medicine and Rehabilitation, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana, USA. [2] Rehabilitation Hospital Indiana, Indianapolis, Indiana, USA.
authors.forename: Arshia Q
authors.initials: AQ
authors.lastname: Ahmad
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK.
authors.forename: Ajith
authors.initials: A
authors.lastname: Sreekantan-Nair
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Department of Neuroradiology, St. George's Hospital, London, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Rich
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neurosciences, University College London Institute of Neurology, London, UK.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Warner
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: David L
authors.initials: DL
authors.lastname: Silver
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008244:Lysophosphatidylcholines / Q000097:blood; D008297:Male; D008831:Microcephaly / Q000097:blood / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D027981:Symporters; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D015525:Fatty Acids, Omega-3; D008244:Lysophosphatidylcholines; C549328:MFSD2A protein, human; D027981:Symporters; D025521:Tumor Suppressor Proteins