Abstract：
Microcephaly is a rare neurodevelopmental disorder characterized by reduced skull circumference and brain volume that occurs sporadically in farm animals. We investigated an early-onset neurodegenerative disorder observed in seven lambs of purebred Kerry Hill sheep. Clinical signs included inability to stand or severe ataxia, convulsions, and early death. Diagnostic imaging and brain necropsy confirmed microcephaly. The pedigree of the lambs suggested monogenic autosomal recessive inheritance. We sequenced the genome of one affected lamb, and comparison with 115 control genomes revealed a single private protein-changing variant. This frameshift variant, MFSD2A: c.285dupA, p.(Asp96fs*9), represents a 1-bp duplication predicted to truncate 80% of the open reading frame. MFSD2A is a transmembrane protein that is essential for maintaining blood-brain barrier homeostasis and plays a key role in regulating brain lipogenesis. Human MFSD2A pathogenic variants are associated with a neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities (NEDMISBA, OMIM 616486). Here we present evidence for the occurrence of a recessively inherited form of microcephaly in sheep due to a loss-of-function variant in MFSD2A (OMIA 002371-9940). To the best of our knowledge, this is the first report of a spontaneous MFSD2A variant in domestic animals.
摘要：
小头畸形是一种罕见的神经发育障碍，其特征是在农场动物中偶尔发生的颅骨周长和脑体积减少。我们调查了在纯种的KerryHill绵羊的七只羔羊中观察到的早发性神经退行性疾病。临床症状包括不能站立或严重共济失调，抽搐,和早逝。诊断成像和脑尸检证实了小头畸形。羔羊的谱系提示单基因常染色体隐性遗传。我们对一只受影响的羔羊的基因组进行了测序，与115个对照基因组进行比较，发现了一个私有蛋白质变化变体。这个移码变体，MFSD2A:c.285dupA,p.(Asp96fs*9)，表示预测将截短80%的开放阅读框的1-bp重复。MFSD2A是一种跨膜蛋白，对于维持血脑屏障稳态至关重要，并在调节脑脂肪生成中起关键作用。人类MFSD2A致病变体与进行性小头畸形的神经发育障碍有关，痉挛,和脑成像异常(NEDMISBA，OMIM616486）。在这里，我们提供了证据，证明由于MFSD2A中的功能丧失变体（OMIA002371-9940），绵羊中出现了隐性遗传形式的小头畸形。据我们所知,这是家养动物中自发的MFSD2A变体的首次报道。
