Department of Neurology, Vanderbilt University, Nashville, TN, United States.
J Neurol Sci. 2013 Dec 15;335(1-2):231-2. doi: 10.1016/j.jns.2013.09.015. Epub 2013 Sep 17.
Mutations in the NIPA1 cause autosomal dominant form of hereditary spastic paraplegia. Allelic heterogeneity of known NIPA1 mutations is quite limited and the most common mutation is c.316G>A resulting in p.G106R protein change. Here we report the first direct evidence of de novo c.316G>A mutation in the same hotspot of the gene in two unrelated patients who had otherwise a prototypical NIPA1-associated phenotype with a severe form of uncomplicated spastic paraplegia. De novo nature of these mutations was confirmed by sequencing both sets of clinically unaffected parents and confirmation of paternity. We also discuss likely molecular mechanisms accounting for recurrent mutations in this segment of the gene. Apparently sporadic patients without a positive family history of hereditary spastic paraplegia need to be also evaluated for possible disease-causing mutations in genes that are inherited in an autosomal dominant fashion.
NIPA1 基因突变导致常染色体显性遗传性痉挛性截瘫。已知 NIPA1 基因突变的等位基因异质性相当有限，最常见的突变是 c.316G>A，导致 p.G106R 蛋白改变。在这里，我们报告了两个无关患者中该基因同一热点处的首个从头 c.316G>A 突变的直接证据，这两个患者除了具有严重的单纯性痉挛性截瘫外，还具有典型的 NIPA1 相关表型。通过对两组临床无影响的父母进行测序并确认亲子关系，证实了这些突变的新生性。我们还讨论了导致该基因这一特定区域反复发生突变的可能分子机制。显然，那些没有遗传性痉挛性截瘫阳性家族史的散发性患者也需要评估是否存在常染色体显性遗传疾病相关基因的致病突变。
