MFSD2A – Autosomal Recessive Primary Microcephaly

MFSD2A encodes Major Facilitator Superfamily Domain containing 2a, an essential endothelial lipid transporter at the blood–brain barrier mediating uptake of lysophosphatidylcholine–docosahexaenoic acid (LPC-DHA). Biallelic loss-of-function variants cause autosomal recessive primary microcephaly 15 (MCPH15, MONDO:0016660), characterized by prenatal head growth arrest, severe microcephaly, and global developmental delay (PMID:32572202). Zebrafish mfsd2aa morphants recapitulate microcephaly and blood–brain barrier breakdown, validating MFSD2A’s role in embryonic brain growth (PMID:26005868).

A multicenter exome sequencing study of 27 affected individuals from 7 unrelated families—including 8 newly ascertained cases—identified biallelic pathogenic MFSD2A alleles under an autosomal recessive inheritance model (PMID:32572202). A representative variant, c.748G>T (p.Val250Phe), segregates in homozygosity with disease in consanguineous kindreds and is absent from population databases. All probands uniformly presented primary microcephaly (HP:0000252) and severe intellectual disability (HP:0001249), with no additional reported segregations beyond the index cases. These data firmly establish MFSD2A as a causative gene for MCPH15.

The variant spectrum includes six novel alleles—two frameshift deletions (c.750_753del (p.Cys251fsTer3), c.1386_1435del (p.Gln462fsTer17)), one canonical splice-site mutation (c.556+1G>A), and three missense changes (p.Val250Phe, p.Arg326His, p.Pro493Leu)—alongside two recurrent missense variants (p.Thr159Met, p.Thr198Met) in multiple families (PMID:32572202). All missense substitutions affect highly conserved residues within transmembrane helices or substrate-binding pockets. No hypomorphic or deep-intronic alleles have been reported, and allele frequencies in gnomAD are negligible, consistent with a rare recessive disorder.

In vitro functional assays in human cell models demonstrated that all patient-derived variants result in significantly reduced MFSD2A protein expression and/or abolished LPC-DHA transport activity, concordant with a loss-of-function mechanism (PMID:32572202). Structural modeling using bacterial MelBSt homologs revealed variant-induced perturbations of cation-coupling and substrate-binding sites. Zebrafish rescue experiments showed that p.Thr159Met and p.Ser166Leu alleles failed to restore normal head size, blood–brain barrier integrity, or survival in mfsd2aa morphants, confirming pathogenicity in vivo (PMID:26005868). Complementary biochemical studies of analogous mutations support a critical charge-balance mechanism for transporter stability.

Additional murine studies reveal that Mfsd2a-null mice exhibit growth restriction, lethality, and defective unfolded protein response in embryonic fibroblasts upon tunicamycin exposure, indicating auxiliary roles in ER stress regulation (PMID:27885588). Reconstitution of wild-type MFSD2A in knockout fibroblasts restores DDIT3 induction, reinforcing specificity. Although direct microcephaly phenotypes in mice are not reported, these findings expand understanding of MFSD2A biology and its potential pleiotropic effects. No conflicting evidence or alternative phenotype associations have been described to date.

Applying ClinGen criteria, the MFSD2A–MCPH15 association meets a Strong gene–disease validity classification, supported by 27 probands from 7 unrelated families, consistent autosomal recessive segregation, a diverse loss-of-function variant spectrum, and concordant functional validation across cell, zebrafish, and mouse models. Genetic evidence alone achieves the maximum tier, and robust experimental data fulfill stringent functional benchmarks. Inclusion of MFSD2A in clinical microcephaly gene panels is warranted for early molecular diagnosis, genetic counseling, and carrier screening. Key Take-home: Biallelic loss-of-function variants in MFSD2A definitively cause autosomal recessive primary microcephaly 15 and should be prioritized in neonatal microcephaly evaluations.

References

• European Journal of Human Genetics • 2020 • Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features. PMID:32572202
• Nature Genetics • 2015 • Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. PMID:26005868
• Human Cell • 2017 • A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin. PMID:27885588

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