A Novel Eight Octapeptide Repeat Insertion in PRNP Causing Prion Disease in a Danish Family
A Novel Eight Octapeptide Repeat Insertion in PRNP Causing Prion Disease in a Danish Family
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DOI：
10.1093/jnen/nlz037
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发表时间：
2019-07-01
影响因子：
3.2
通讯作者：
Lund, Eva Lobner
中科院分区：
文献类型：
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作者：
Areskeviciute, Ausrine;Hogh, Peter;Lund, Eva Lobner
朊病毒蛋白基因 (PRNP) 中发现的八肽重复插入 (OPRI) 构成了与遗传性朊病毒疾病相关的致病性突变亚组，其标志是错误折叠的朊病毒蛋白。 OPRI 中的重复次数与不同的疾病表型相关。然而，由于病例的稀有性和疾病表现的异质性，这些变异的识别和分类一直很困难。在这里，我们报告了第一个丹麦家族，也是全球第五个家族，携带一种新型 8-OPRI，其具有额外 8 个插入片段的独特序列：R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4。该突变是在 PRNP 基因密码子 129 处编码蛋氨酸的等位基因上发现的。临床外显子组测序显示，没有其他痴呆相关基因存在致病性改变。突变携带者在三十出头时出现症状，但病程从5年到11年不等。伴有精神和运动症状的进行性痴呆是最突出的临床特征。对其他 4 个报道的 8-OPRI 家族的临床、病理和遗传特征进行了回顾，并与丹麦家族的研究结果进行了比较。
Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family.