CCDC88A mutations cause PEHO-like syndrome in humans and mouse.
CCDC88A mutations cause PEHO-like syndrome in humans and mouse.
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DOI：
10.1093/brain/aww014
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Woods CG
中科院分区：
文献类型：
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作者：
Nahorski MS;Asai M;Wakeling E;Parker A;Asai N;Canham N;Holder SE;Chen YC;Dyer J;Brady AF;Takahashi M;Woods CG
进行性脑病伴水肿、心律失常和神经萎缩（PEHO）是一种罕见的神经退行性疾病，病因不明。Nahorski等人。在编码肌动蛋白结合蛋白Girdin的CCDC88A中鉴定出第一个致病隐性突变。Ccdc88a基因敲除小鼠的表型和脑解剖结构与人类PEHO综合征相似。进行性脑病伴水肿、心律失常和神经萎缩（PEHO）是一种罕见的神经退行性疾病，病因不明。Nahorski等人。在编码肌动蛋白结合蛋白Girdin的CCDC88A中鉴定出第一个致病隐性突变。Ccdc88a基因敲除小鼠的表型和脑解剖结构与人类PEHO综合征相似。进行性脑病伴水肿、低心律失常和视神经萎缩（PEHO）综合征是一种罕见的孟德尔表型，包括严重发育迟缓、早发性癫痫发作、视神经/小脑萎缩、足部水肿和早期死亡。非典型病例通常被称为peho样，与“早期婴儿癫痫性脑病”有重叠。PEHO被认为是隐性的，但令人惊讶的是，自1991年首次描述以来，没有任何致病隐性基因被描述。因此，我们报告了一个具有PEHO表型的多重近亲家族，其中受影响的个体在CCDC88A （c.2313delT, p.Leu772*ter）中具有纯合的移框缺失。从患者淋巴细胞中提取的cDNA分析意外地未能显示非义介导的衰变，并且我们证明该突变产生缺乏关键的CCDC88A c端一半（girdin）的截断蛋白。为了进一步研究CCDC88A在人类神经发育中的可能作用，我们重新检查了CCDC88A基因敲除幼崽的行为和神经解剖学。这些小鼠有内侧颞叶癫痫、小头畸形和胼胝体缺陷，并在出生后第21天出现小头畸形；这些老鼠在很小的时候就死了。由于小鼠敲除表型与人类PEHO表型相似，这表明CCDC88A的缺失是PEHO表型的一个原因，并且CCDC88A对于正常人类神经发育的多个方面都是必不可少的。
P rogressive E ncephalopathy with oedema, H ypsarrhythmia and O ptic atrophy (PEHO) is a rare, neurodegenerative disorder of unknown aetiology. Nahorski et al . identify the first causative recessive mutation in CCDC88A , which encodes the actin-binding protein Girdin. The phenotype and brain anatomy of the Ccdc88a knockout mouse resemble those of human PEHO syndrome. P rogressive E ncephalopathy with oedema, H ypsarrhythmia and O ptic atrophy (PEHO) is a rare, neurodegenerative disorder of unknown aetiology. Nahorski et al . identify the first causative recessive mutation in CCDC88A , which encodes the actin-binding protein Girdin. The phenotype and brain anatomy of the Ccdc88a knockout mouse resemble those of human PEHO syndrome. Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with ‘early infantile epileptic encephalopathy’. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.