Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis
Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis
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DOI：
10.1093/brain/awn366
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发表时间：
2009-03-01
期刊：
影响因子：
14.5
通讯作者：
Lehesjoki, Anna-Elina
中科院分区：
文献类型：
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作者：
Kousi, Maria;Siintola, Eija;Lehesjoki, Anna-Elina
神经元蜡样质脂褐质沉积症是儿童期最常见的神经退行性疾病，其特征是自发荧光物质主要在神经元中积聚。虽然临床上相当统一，但变异型婴儿晚发型NCL（vLINCL）在遗传上是异质性的，迄今已确定了四个主要的潜在基因。我们评估了119例vLINCL患者的遗传背景，并特别分析了最近报道的80例患者的CLN 7/MFSD 8基因突变。从CLN 7/MFSD 8突变阳性患者收集临床数据。在不同种族来源的患者中鉴定了8种新的CLN 7/MFSD 8突变和CLN 1/PPT 1、CLN 2/TPP 1、CLN 5、CLN 6和CLN 8基因中的7种新突变。来自前捷克斯洛伐克的一组重要的罗姆人患者被证明在CLN 7/MFSD 8中携带c.881CA（p.Thr294Lys）突变，这可能是由于创始人效应。除了一个例外，CLN 7/MFSD 8突变阳性患者呈现与其他vLINCL形式不可区分的表型。在CLN 7/MFSD 8中具有框内氨基酸取代突变的一名患者中，疾病发作较晚，并且疾病过程不如变异的晚婴儿NCL具有侵袭性。我们的研究结果将CLN 7/MFSD 8突变的总数提高到14个，大多数家庭都有私人突变。我们的研究证实，CLN 7/MFSD 8缺陷并不像最初预期的那样仅限于土耳其人群，而是不同人群中NCL的一个相对常见的原因。CLN 7/MFSD 8应被认为是一种诊断替代方案，不仅在变异的婴儿晚期，而且在具有更长病程的晚发型NCL形式中。土耳其存在大量的NCL患者，其中潜在的遗传缺陷仍有待确定。
The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881CA (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined.