Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease
Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease
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DOI：
10.1038/s41588-019-0459-y
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发表时间：
2019-08-01
期刊：
影响因子：
30.8
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Sone, Jun;Mitsuhashi, Satomi;Sobue, Gen
神经元核内包涵体病（NIID）是一种进行性神经退行性疾病，其特征是神经元和体细胞中出现嗜酸性透明核内包涵体。 NIID 的广泛临床表现使得生前诊断变得困难(1-8)，但皮肤活检可以实现生前诊断(9-12)。大约 140 例 NIID 病例中，平均发病年龄为 59.7 岁，其中大部分为散发病例和一些家族病例。通过对一个大型 NIID 家族与多个受影响成员（家族 1）进行连锁图谱分析，我们在 1p22.1-q21.3 处确定了一个 58.1 Mb 的连锁区域，其优势分数的最大对数为 4.21。通过长读长测序，我们在所有受影响的家族成员中发现了 NOTCH2NLC（Notch 2 N 末端，如 C）5' 区域的 GGC 重复扩增。此外，我们在 8 个无亲属关系的 NIID 家庭和 40 个零星 NIID 病例中发现了类似的扩展。我们在患者的成纤维细胞中观察到异常的反义转录物，但未受影响的个体中却没有观察到。这项工作表明，人类特异性NOTCH2NLC（一种通过节段复制进化而来的基因）的重复扩增会导致人类疾病。
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes antemortem diagnosis difficult(1-8), but skin biopsy enables its antemortem diagnosis(9-12). The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.