Missense mutations in the regulatory domain of PKCγ:: A new mechanism for dominant nonepisodic cerebellar ataxia
Missense mutations in the regulatory domain of PKCγ:: A new mechanism for dominant nonepisodic cerebellar ataxia
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DOI：
10.1086/373883
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发表时间：
2003-04-01
影响因子：
9.8
通讯作者：
Raskind, WH
中科院分区：
文献类型：
--
作者：
Chen, DH;Brkanac, Z;Raskind, WH
我们报告一个nonepisodic常染色体显性（AD）脊髓小脑共济失调（SCA）不是由核苷酸重复扩增，这是我们所知，第一个这样的SCA。AD SCA目前包括一组大于或等于16种遗传上不同的神经退行性疾病，所有这些疾病的特征都是步态和肢体进行性不协调以及言语和眼球运动障碍。已知基因的九种SCA中有六种是由编码多聚谷氨酰胺束的CAG扩增产生的。非编码CAG、CTG和ATTCT扩展负责其他三个SCA。大约30%的SCA家系与已知的基因座不连锁。我们最近将一个AD SCA家系（AT 08）的基因定位于染色体19q13.4-qter。一个特别引人注目的候选基因，PRKCG，编码蛋白激酶C γ（PKC γ），丝氨酸/苏氨酸激酶家族的成员。在AT 08家族的一名受累成员和一组39名不相关的共济失调患者中对PRKCG的整个编码区进行测序，这些患者不归因于三核苷酸扩增。三个不同的非保守性错义突变的高度保守的残基C1，半胱氨酸丰富的区域的蛋白质，被发现在家庭AT 08，另一个家族性病例，和散发病例。在两个家庭中，突变与疾病共分离。结构建模预测，这些氨基酸取代中的两个将严重废除蛋白质的锌结合或佛波酯结合能力。对来自AT 08家族受影响成员的小脑组织的免疫组织化学研究表明，浦肯野细胞中PKC和共济失调蛋白1的染色减少，而钙结合蛋白的染色保留。这些结果强烈支持遗传性共济失调中神经元细胞功能障碍和死亡的新机制，并表明PKC γ相关和聚谷氨酰胺相关神经变性可能存在共同途径。
We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of greater than or equal to16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts. Noncoding CAG, CTG, and ATTCT expansions are responsible for three other SCAs. Approximately 30% of families with SCA do not have linkage to the known loci. We recently mapped the locus for an AD SCA in a family (AT08) to chromosome 19q13.4-qter. A particularly compelling candidate gene, PRKCG, encodes protein kinase C gamma (PKCgamma), a member of a family of serine/threonine kinases. The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions. Three different nonconservative missense mutations in highly conserved residues in C1, the cysteine-rich region of the protein, were found in family AT08, another familial case, and a sporadic case. The mutations cosegregated with disease in both families. Structural modeling predicts that two of these amino acid substitutions would severely abrogate the zinc-binding or phorbol ester-binding capabilities of the protein. Immunohistochemical studies on cerebellar tissue from an affected member of family AT08 demonstrated reduced staining for both PKCg and ataxin 1 in Purkinje cells, whereas staining for calbindin was preserved. These results strongly support a new mechanism for neuronal cell dysfunction and death in hereditary ataxias and suggest that there may be a common pathway for PKCgamma-related and polyglutamine-related neurodegeneration.