Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

包含2a（MFSD2A）的主要促进者超家族结构域是血脑屏障中必需的内皮脂质转运蛋白。双等位基因变异影响MFSD2A中的功能引起常染色体隐性隐性原发性小头畸形15（MCPH15，OMIM＃616486）。我们试图扩展我们对MCPH15表型谱的了解，并证明MFSD2A转运蛋白失活的潜在机制。我们对一系列27例MCPH15病例的临床和神经放射学特征进行了详细分析，其中包括来自七个无关家庭的八名新个体。通过外显子组测序（ES）进行遗传研究。对人类Mfsd2a模型的结构见解和体外生化分析用于研究已鉴定变体的功能影响。所有患者均患有原发性小头畸形和严重的发育延迟。脑部MRI显示不同程度的白质减少，心室扩大，call骨发育不全以及桥脑和Vermian增生。MFSD2A变体（NG_053084.1，NM_032793.5：c.556 + 1G> A，c.748G> T; p。（Val250Phe），c.750_753del; p。（Cys251SerfsTer3），c.977G> A; p。（ Arg326His），c.1386_1435del; p。（Gln462HisfsTer17）和c.1478C> T; p。（Pro493Leu））和两个循环变体（NM_032793.5：c.593C> T; p。（Thr198Met）和c.476C > T;第（Thr159Met）页。所有这些变体和先前报道的NM_032793.5：c.490C> A; p。（Pro164Thr）导致MFSD2A表达降低和/或转运活性降低。我们的研究进一步描绘了MCPH15的表型谱，完善了其临床和神经放射学特征，并支持MFSD2A缺乏会导致早期产前大脑发育中断。我们还显示，尽管转运蛋白活动正常，但MFSD2A表达不佳是MCPH15中的一种相关发病机制。