Intragenic MFSD8 duplication and histopathological findings in a rabbit with neuronal ceroid lipofuscinosis

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Matthias Christen, Katharina M. Gregor, Ariane Böttcher-Künneke, Mara S. Lombardo, Wolfgang Baumgärtner, Vidhya Jagannathan, Christina Puff, Tosso Leeb
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Abstract

Neuronal ceroid lipofuscinoses (NCL) are among the most prevalent neurodegenerative disorders of early life in humans. Disease-causing variants have been described for 13 different NCL genes. In this study, a refined pathological characterization of a female rabbit with progressive neurological signs reminiscent of NCL was performed. Cytoplasmic pigment present in neurons was weakly positive with Sudan black B and autofluorescent. Immunohistology revealed astrogliosis, microgliosis and axonal degeneration. During the subsequent genetic investigation, the genome of the affected rabbit was sequenced and examined for private variants in NCL candidate genes. The analysis revealed a homozygous ~10.7 kb genomic duplication on chromosome 15 comprising parts of the MFSD8 gene, NC_013683.1:g.103,727,963_103,738,667dup. The duplication harbors two internal protein coding exons and is predicted to introduce a premature stop codon into the transcript, truncating ~50% of the wild-type MFSD8 open reading frame encoding the major facilitator superfamily domain containing protein 8, XP_002717309.2:p.(Glu235Leufs*23). Biallelic loss-of-function variants in MFSD8 have been described to cause NCL7 in human patients, dogs and a single cat. The available clinical and pathological data, together with current knowledge about MFSD8 variants and their functional impact in other species, point to the MFSD8 duplication as a likely causative defect for the observed phenotype in the affected rabbit.

Abstract Image

神经细胞类脂膜炎兔的基因内 MFSD8 重复和组织病理学发现。
神经细胞类脂膜炎(NCL)是人类早期最常见的神经退行性疾病之一。已有 13 种不同的 NCL 基因被描述为致病变体。在本研究中,我们对一只患有类似 NCL 的进行性神经症状的雌性兔子进行了精细的病理特征描述。神经元中的细胞质色素在苏丹黑 B 诱导下呈弱阳性,并有自发荧光。免疫组织学检查显示星形胶质细胞增生、小胶质细胞增生和轴突变性。在随后的基因调查中,对患病兔子的基因组进行了测序,并检查了 NCL 候选基因中的私人变异。分析结果显示,15 号染色体上有一个同源的 ~10.7 kb 基因组重复,包括 MFSD8 基因的部分,NC_013683.1:g.103,727,963_103,738,667dup。该重复包含两个内部蛋白编码外显子,预计会在转录本中引入一个过早终止密码子,截断野生型 MFSD8 开放阅读框的约 50%,该开放阅读框编码含主要促进剂超家族结构域蛋白 8,XP_002717309.2:p.(Glu235Leufs*23)。据描述,MFSD8 的双倍功能缺失变体可导致人类患者、狗和一只猫出现 NCL7。现有的临床和病理数据,以及目前对其他物种中 MFSD8 变异及其功能影响的了解,都表明 MFSD8 复制可能是受影响兔子所观察到的表型的致病缺陷。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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