日前,，美國(guó)華盛頓大學(xué)醫(yī)學(xué)院的研究人員發(fā)現(xiàn)DNAJC5基因變異與庫夫斯病有關(guān),，該基因與大腦中神經(jīng)細(xì)胞突觸之間的信號(hào)傳遞有關(guān),。其最新研究成果"Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis"發(fā)表在最新一期的《公共科學(xué)圖書館—綜合》網(wǎng)絡(luò)版上。
研究人員通過對(duì)懷疑有阿爾茨海默病的家族成員研究發(fā)現(xiàn),，有種基因可能與一種罕見的可導(dǎo)致記憶力喪失,、活動(dòng)受影響、甚至過早死亡的疾病有關(guān),。
這種疾病稱為庫夫斯病,，主要影響中年人,，但相關(guān)的疾病也會(huì)影響兒童和嬰幼兒?？茖W(xué)家們說,，他們的發(fā)現(xiàn)為庫夫斯病的遺傳檢測(cè)和癡呆癥的治療鋪平了道路。癡呆是庫夫斯病和其它神經(jīng)退行性疾病的重要特征,，如阿爾茨海默病,。研究人員發(fā)現(xiàn),，DNAJC5基因變異與庫夫斯病有關(guān),。過去從沒有將這種基因與任何人類疾病聯(lián)系起來。該基因與大腦中神經(jīng)細(xì)胞突觸之間的信號(hào)傳遞有關(guān),。
研究人員布魯諾貝尼特斯說,，突觸功能異常是其它形式癡呆的基礎(chǔ)，這種導(dǎo)致庫夫斯病的基因有可能為這類疾病的研究開辟新的途徑,，因?yàn)樗梢蕴峁┯嘘P(guān)癡呆的一些新的信息,。因此，這一發(fā)現(xiàn)的意義超出了庫夫斯病本身,。
庫夫斯病是神經(jīng)元蠟樣脂褐質(zhì)沉積癥（NCLs）之一,，世界上每10萬人當(dāng)中NCLs發(fā)病人數(shù)為2-4人。庫夫斯病占這類疾病的比例不足10%,，主要影響成年人,，但也會(huì)在6-60歲人中發(fā)病，而且往往是致命的,。其它相關(guān)疾病,，如貝敦氏病和Jansky-Bielschowsky 病（比-詹二氏病,，嬰兒型黑蒙性癡呆)分別影響兒童和嬰幼兒,。大多數(shù)NCLs是隱性遺傳自父母。
成年人NCLs的常見癥狀包括癡呆,、智力遲鈍,、運(yùn)動(dòng)障礙、抽搐和肌肉不協(xié)調(diào),。目前對(duì)這種疾病還沒有治療辦法,，但有一些藥物可以治療癥狀，如抽搐,。
研究包括來自同一家族的兩名庫夫斯病人,。最初他們因?yàn)槌霈F(xiàn)懷疑與阿爾茨海默病有關(guān)的記憶問題就診于華盛頓大學(xué)阿爾茨海默病研究中心。這些疾病的早期癥狀會(huì)非常相似,，但通過測(cè)量細(xì)胞內(nèi)脂色素的累積情況可以將它們區(qū)分開來,。脂色素由脂肪和蛋白組成,，在紫外線顯微鏡下觀察呈黃綠色。庫夫斯病患者體內(nèi)多數(shù)細(xì)胞的脂色素水平會(huì)出現(xiàn)異常,。研究人員對(duì)兩位庫夫斯病患者和他們沒有患病親屬的DNA作了排序,，并將結(jié)果進(jìn)行了比較。通過只對(duì)產(chǎn)生蛋白的DNA區(qū)域進(jìn)行分析的全外顯子測(cè)序技術(shù),，研究人員對(duì)導(dǎo)致庫夫斯病的遺傳改變進(jìn)行了追蹤,。
由于每個(gè)人中大約存在3000種變異，要想找出引起一種疾病的惟一DNA變異幾乎是不可能的,。但研究人員通過對(duì)兩名患者和他們親屬的DNA進(jìn)行比較后將變異基因的數(shù)量縮小到了24個(gè),。通過對(duì)更多家庭成員進(jìn)行DNA研究，他們挑選出了3種變異基因,。研究人員最后發(fā)現(xiàn)有兩種基因變異也存在于一些健康的人中,，因此剩下的一種變異基因就與庫夫斯病有關(guān)。
研究人員還對(duì)受庫夫斯病影響的其它家族進(jìn)行了基因排序,，并發(fā)現(xiàn)了其它的遺傳變異,。但這些變異都位于DNAJC5基因上，而且會(huì)引起與大腦中神經(jīng)細(xì)胞信號(hào)有關(guān)蛋白的改變,。
這一發(fā)現(xiàn)使得通過遺傳測(cè)試告訴庫夫斯病患者親屬他們將來是否會(huì)患病成為可能,，另外還可以幫助醫(yī)生診斷主要影響兒童的一些相關(guān)疾病。（生物谷 Bioon.com）
doi:10.1371/journal.pone.0026741
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Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis
Bruno A. Benitez1, David Alvarado2, Yefei Cai1, Kevin Mayo1, Sumitra Chakraverty1, Joanne Norton1, John C. Morris3, Mark S. Sands2,4, Alison Goate1,3,4,5, Carlos Cruchaga1,4*
We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.
