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Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome
- Source :
- Nature Genetics. 47:809-813
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.
- Subjects :
- Male
Microcephaly
Adolescent
Mutation, Missense
Biology
Blood–brain barrier
medicine.disease_cause
Article
Consanguinity
Fatty Acids, Omega-3
Genetics
medicine
Animals
Humans
Child
Omega 3 fatty acid
Genetic Association Studies
Zebrafish
Mice, Knockout
chemistry.chemical_classification
Mutation
Symporters
Tumor Suppressor Proteins
Brain
Infant
Fatty acid
Biological Transport
Morphant
Syndrome
Human brain
medicine.disease
Major facilitator superfamily
HEK293 Cells
medicine.anatomical_structure
chemistry
Biochemistry
Blood-Brain Barrier
Case-Control Studies
Child, Preschool
Female
Genes, Lethal
lipids (amino acids, peptides, and proteins)
Subjects
Details
- ISSN :
- 15461718 and 10614036
- Volume :
- 47
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi.dedup.....0f82ca55913cf53465ec03077434c48d