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

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Authors
Vafa Alakbarzade, Abdul Hameed, Debra Q Y Quek, Barry A Chioza, Emma L Baple, Amaury Cazenave-Gassiot, Long N Nguyen, Markus R Wenk, Arshia Q Ahmad, Ajith Sreekantan-Nair, Michael N Weedon, Phil Rich, Michael A Patton, Thomas T Warner, David L Silver, Andrew H Crosby
Year
2015
DOI
10.1038/ng.3313
Subject
Genetics

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The major pathway by which the brain obtains essential  omega-3 fatty acids from the circulation is through a sodiumdependent 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.

We investigated an extensive Pakistani pedigree (Fig. 1a) comprising individuals with an autosomal recessively inherited progressive neurological condition in which the cardinal features included microcephaly, spastic quadriparesis and intellectual disability with absent speech. Neuroimaging was available for two affected individuals and showed a consistent radiological phenotype with microcephaly and a profound lack of posterior white matter (Fig. 1b and Supplementary

Table 1). To map the disease-associated locus, we used DNA samples from affected and unaffected family members to perform genomewide SNP genotyping, assuming that a founder mutation was responsible. This mapping identified a single notable homozygous region of 19.9 Mb on chromosome 1p34 (maximum logarithm of odds (LOD) = 7.3) shared by all affected individuals (Supplementary

Fig. 1). The region, considered likely to correspond to the disease locus, is delimited by the recombinant SNP markers rs3767088 and rs1033729 and contains 395 genes. To identify the causative mutation, we performed whole-exome sequence analysis of a single affected individual (II:3) to identify potential disease-causing variants. After filtering, we identified only one likely deleterious variant within the critical region, in exon 10 of the MFSD2A gene (encoding major facilitator superfamily domain–containing 2a; c.1016C>T, NC_000001.11: g.39967632C>T; p.Ser339Leu). We did not detect any likely deleterious sequence variants in other genes responsible for microcephaly, including the microcephalin genes, all of which are located outside of the homozygous critical interval, nor in SLC2A1 (GLUT1), also located on chromosome 1p, which was further excluded by dideoxy sequence analysis. The MFSD2A sequence variant affected a stringently conserved amino acid residue and cosegregated with the disease phenotype (Fig. 1), was predicted to be highly damaging using standard programs (PROVEAN score < −2.5), and was absent from the online genomic dbSNP 141, 1000 Genomes Project and National

Heart, Lung, and Blood Institute (NHLBI) ESP6500 databases.

We previously identified MFSD2A as the major transporter for uptake of the omega-3 fatty acid docosahexaenoic acid (DHA) into the brain, which is selectively expressed in the blood-brain epithelium1.

MFSD2A is a plasma membrane protein that belongs to the major facilitator superfamily of secondary transporters, which have 12 membrane-spanning domains2. We recently showed that MFSD2A transports DHA and other long-chain fatty acids into the brain in the chemical form of LPC, defining MFSD2A as the first characterized sodium-dependent facilitative transporter of LPCs1. Mfsd2a-knockout mice are deficient for DHA in the brain and present with severe

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

Vafa Alakbarzade1,2,12, Abdul Hameed3,12, Debra Q Y Quek4,12, Barry A Chioza1,12, Emma L Baple1,5,6,12,

Amaury Cazenave-Gassiot7, Long N Nguyen4, Markus R Wenk7, Arshia Q Ahmad8,9, Ajith Sreekantan-Nair1,

Michael N Weedon1, Phil Rich10, Michael A Patton1,11, Thomas T Warner2, David L Silver4 & Andrew H Crosby1 1Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK. 2Reta Lila Weston Institute of Neurological

Studies, Department of Molecular Neurosciences, University College London Institute of Neurology, London, UK. 3Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan. 4Signature Research Program in Cardiovascular and Metabolic Disorders, Duke–National University of Singapore Graduate Medical

School, Singapore. 5Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK. 6Wessex Clinical Genetics Service,

Princess Anne Hospital, Southampton, UK. 7Life Sciences Institute, National University of Singapore, Singapore. 8Department of Physical Medicine and Rehabilitation,

Indiana University–Purdue University Indianapolis (IUPUI), Indianapolis, Indiana, USA. 9Rehabilitation Hospital Indiana, Indianapolis, Indiana, USA. 10Department of

Neuroradiology, St. George’s Hospital, London, UK. 11Southwest Thames Regional Genetics Service, St George’s Healthcare National Health Service (NHS) Trust, London,

UK. 12These authors contributed equally to this work. Correspondence should be addressed to A.H.C. (a.h.crosby@exeter.ac.uk) or D.L.S. (david.silver@duke-nus.edu.sg).