Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse
Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse
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DOI：
10.1086/338190
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发表时间：
2002-02-01
影响因子：
9.8
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
Gao, HL;Boustany, RMN;MacDonald, ME
CLN 6基因可导致变异的晚期婴儿神经元蜡样质脂褐质沉积症（vLINCL），这是一种以失明、癫痫发作和认知能力下降为特征的遗传性神经退行性疾病，该基因定位于15 q21 -23。我们已经使用了多等位基因标记跨越这个类似的4-Mb的候选间隔，以揭示一个核心单倍型，在哥斯达黎加家庭与vLINCL共享，但不是在委内瑞拉的亲属，突出了一个地区可能包含CLN 6缺陷。从最小区域的基因的系统比较发现了一个新的候选人，FLJ 20561，表现出特定于不同的疾病染色体的DNA序列的变化：在外显子3的G T颠换，引入终止密码子的哥斯达黎加单倍型，和密码子缺失在外显子5，消除了委内瑞拉染色体上的保守的酪氨酸残基。此外，在nclf小鼠，这表现出隐性NCL样疾病的小鼠同源物的测序，披露了第三个病变-在外显子4的额外的碱基对，在nclf染色体上产生移码截短。因此，新的类似于36-kD CLN 6基因产物增加了一组有趣的不相关的跨膜蛋白，其缺陷导致小鼠和人的NCL。
The CLN6 gene that causes variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a recessively inherited neurodegenerative disease that features blindness, seizures, and cognitive decline, maps to 15q21-23. We have used multiallele markers spanning this similar to4-Mb candidate interval to reveal a core haplotype, shared in Costa Rican families with vLINCL but not in a Venezuelan kindred, that highlighted a region likely to contain the CLN6 defect. Systematic comparison of genes from the minimal region uncovered a novel candidate, FLJ20561, that exhibited DNA sequence changes specific to the different disease chromosomes: a G T transversion in exon 3, introducing a stop codon on the Costa Rican haplotype, and a codon deletion in exon 5, eliminating a conserved tyrosine residue on the Venezuelan chromosome. Furthermore, sequencing of the murine homologue in the nclf mouse, which manifests recessive NCL-like disease, disclosed a third lesion-an extra base pair in exon 4, producing a frameshift truncation on the nclf chromosome. Thus, the novel similar to36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man.