溶酶体酶靶向途径突变与持续性口吃。
Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering.
机构信息
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
出版信息
N Engl J Med. 2010 Feb 25;362(8):677-85. doi: 10.1056/NEJMoa0902630. Epub 2010 Feb 10.
BACKGROUND
Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12.
METHODS
We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America.
RESULTS
We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms.
CONCLUSIONS
Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.
背景
口吃是一种病因不明的障碍，其特征是言语流畅性出现重复、延长和中断。遗传因素与这种障碍有关，以前对口吃的研究已经确定了与 12 号染色体标记的联系。
方法
我们分析了来自巴基斯坦的有血缘关系的家庭的 12q23.3 基因组区域，其中一些成员患有非综合征性口吃，以及来自巴基斯坦和北美的无关病例和对照受试者。
结果
我们在一个大的、有血缘关系的巴基斯坦家庭中发现了 N-乙酰葡萄糖胺-1-磷酸转移酶基因（GNPTAB）的错义突变，该基因编码 GlcNAc-磷酸转移酶（GNPT[EC 2.7.8.15]）的α和β催化亚基，该突变与口吃有关。该突变发生在大约 10%受影响的巴基斯坦家庭的成员中，但在来自未受影响的无关巴基斯坦对照受试者的 192 条染色体中仅出现一次，在来自未受影响的无关北美对照受试者的 552 条染色体中未观察到。GNPTAB 中的这种突变和另外三个突变发生在无关的口吃受试者中，但不在对照受试者中。我们还在亚洲和欧洲血统的受影响受试者中发现了 GNPTG 基因中的三个突变，但在对照受试者中没有发现。此外，我们在其他受影响的受试者中发现了 NAGPA 基因中的三个突变，但在对照受试者中没有发现。这些基因编码产生甘露糖-6-磷酸信号的酶，该信号指导一组不同的水解酶到达溶酶体。该系统的缺陷与粘脂贮积症有关，粘脂贮积症是一种罕见的溶酶体贮积症，最常与骨骼、结缔组织和神经系统症状有关。
结论
非综合征性口吃的易感性与控制溶酶体代谢的基因变异有关。
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