Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features.
Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features.
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DOI：
10.1038/s41431-020-0669-x
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Silver DL
中科院分区：
文献类型：
--
作者：
Scala M;Chua GL;Chin CF;Alsaif HS;Borovikov A;Riazuddin S;Riazuddin S;Chiara Manzini M;Severino M;Kuk A;Fan H;Jamshidi Y;Toosi MB;Doosti M;Karimiani EG;Salpietro V;Dadali E;Baydakova G;Konovalov F;Lozier E;O'Connor E;Sabr Y;Alfaifi A;Ashrafzadeh F;Striano P;Zara F;Alkuraya FS;Houlden H;Maroofian R;Silver DL
主要促进剂超家族结构域包含2a（MFSD 2A）是血脑屏障上一种重要的内皮脂质转运蛋白。影响MFSD 2A功能的双等位基因变体导致常染色体隐性原发性小头畸形15（MCPH 15，OMIM# 616486）。我们试图扩大我们对MCPH 15表型谱的了解，并证明MFSD 2A转运蛋白失活的潜在机制。我们对27例MCPH 15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7个无关家族的8个新个体。通过外显子组测序（ES）进行遗传调查。使用对人Mfsd 2a模型的结构见解和体外生物化学测定来研究所鉴定的变体的功能影响。所有患者均有原发性小头畸形和严重发育迟缓。脑部MRI显示不同程度的白色物质减少、脑室扩大、胼胝体发育不全、脑桥和小脑蚓部发育不全。ES导致鉴定出六种新的双等位基因MFSD 2A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.（Pro493 Leu））和两种复发性变体（NM_032793.5：c.593C>T; p.（Thr198Met）和c.476C>T; p.（Thr159Met））。所有这些变体和之前报道的NM_032793.5：c.490C>A; p.（Pro 164 Thr）导致MFSD 2A表达和/或转运活性降低。我们的研究进一步描绘了MCPH 15的表型谱，完善了其临床和神经放射学特征，并支持MFSD 2A缺陷导致早期产前脑发育中断。我们还表明，尽管正常的转运蛋白活性，但MFSD 2A表达不佳是MCPH 15的相关病理机制。
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.
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影响因子：
64.8
作者：
Nguyen, Long N.;Ma, Dongliang;Silver, David L.
通讯作者：
Silver, David L.
影响因子：
2.2
作者：
Harel, Tamar;Quek, Debra Q. Y.;Edvardson, Shimon
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Edvardson, Shimon
影响因子：
11
作者：
Riazuddin, S.;Hussain, M.;Riazuddin, S.
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Riazuddin, S.
影响因子：
16.2
作者：
Andreone BJ;Chow BW;Tata A;Lacoste B;Ben-Zvi A;Bullock K;Deik AA;Ginty DD;Clish CB;Gu C
通讯作者：
Gu C
影响因子：
2.2
作者：
Hu, Hua;Du, Fei;Zhang, Weiguo
通讯作者：
Zhang, Weiguo