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Neurogenetics. 2018 Jul 24. doi: 10.1007/s10048-018-0556-6. [Epub ahead of print]

Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination.

Author information

1
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, POB 12000, 9112001, Jerusalem, Israel. tamarhe@hadassah.org.il.
2
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore.
3
Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD 7, Singapore, 117597, Singapore.
4
Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.
5
Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis St., Matrix No. 07-01, Singapore, 138671, Singapore.
6
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
7
Centre for Computational Biology, DUKE-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
8
Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
9
Child Developmental Center, Clalit Health Services, Jerusalem, Israel.
10
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, POB 12000, 9112001, Jerusalem, Israel.
11
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
12
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore. david.silver@duke-nus.edu.sg.

Abstract

The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter. We describe two siblings with shared parental ancestry, in whom we identified a homozygous missense mutation (c.1205C > A; p.Pro402His) in MFSD2A. Both affected individuals had microcephaly, hypotonia, appendicular spasticity, dystonia, strabismus, and global developmental delay. Neuroimaging revealed paucity of white matter with enlarged lateral ventricles. Plasma lysophosphatidylcholine (LPC) levels were elevated, reflecting reduced brain transport. Cell-based studies of the p.Pro402His mutant protein indicated complete loss of activity of the transporter despite the non-lethal, attenuated phenotype. The aggregate data of MFSD2A-associated genotypes and phenotypes suggest that additional factors, such as nutritional supplementation or modifying genetic factors, may modulate the severity of disease and call for consideration of treatment options for affected individuals.

KEYWORDS:

Blood-brain barrier; Docosahexanoic acid; Lysolipid transporters; Lysophosphatidylcholine; MFSD2A; Microcephaly

PMID:
30043326
DOI:
10.1007/s10048-018-0556-6

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