Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome

被引：197

作者：

Guemez-Gamboa, Alicia ^{[1
,2
]}

Nguyen, Long N. ^{[3
]}

Yang, Hongbo ^{[4
]}

Zaki, Maha S. ^{[5
]}

Kara, Majdi ^{[6
]}

Ben-Omran, Tawfeg ^{[7
]}

Akizu, Naiara ^{[1
,2
]}

Rosti, Rasim Ozgur ^{[1
,2
]}

Rosti, Basak ^{[1
,2
]}

Scott, Eric ^{[1
,2
]}

Schroth, Jana ^{[1
,2
]}

Copeland, Brett ^{[1
,2
]}

Vaux, Keith K. ^{[1
,2
]}

Cazenave-Gassiot, Amaury ^{[8
]}

Quek, Debra Q. Y. ^{[3
]}

Wong, Bernice H. ^{[3
]}

Tan, Bryan C. ^{[3
]}

Wenk, Markus R. ^{[8
]}

Gunel, Murat ^{[9
]}

Gabriel, Stacey ^{[10
]}

Chi, Neil C. ^{[4
]}

Silver, David L. ^{[3
]}

Gleeson, Joseph G. ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92103 USA

[2] Howard Hughes Med Inst, Chevy Chase, MD USA

[3] Duke Natl Univ Singapore, Grad Sch Med, Signature Res Program Cardiovasc & Metab Dis, Singapore, Singapore

[4] Univ Calif San Diego, La Jolla, CA 92093 USA

[5] Natl Res Ctr, Human Genet & Genome Res Div, Dept Clin Genet, Cairo, Egypt

[6] Tripoli Childrens Hosp, Dept Pediat, Tripoli, Libya

[7] Hamad Med Corp, Dept Pediat, Clin & Metab Genet Div, Doha, Qatar

[8] Natl Univ Singapore, Dept Biochem, Singapore 117548, Singapore

[9] Yale Univ, Sch Med, Dept Neurosurg Neurobiol & Genet, Yale Program Neurogenet, New Haven, CT USA

[10] MIT & Harward, Broad Inst, Cambridge, MA USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 07期

基金：

新加坡国家研究基金会; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

FATTY-ACID COMPOSITION; DOCOSAHEXAENOIC ACID; BARRIER; PERICYTES; NEUROGENESIS; EXPRESSION; DISCOVERY; MOUSE;

D O I：

10.1038/ng.3311

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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(1,2). 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(3). 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.

引用

页码：809 / +

页数：7

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