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 ante-mortem diagnosis difficult1,2,3,4,5,6,7,8, but skin biopsy enables its ante-mortem diagnosis9,10,11,12. 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Long-read sequencing data have been deposited in the Human Genetic Variation Database under accession ID: HGV0000008.
Lindenberg, R., Rubinstein, L. J., Herman, M. M. & Haydon, G. B. A light and electron microscopy study of an unusual widespread nuclear inclusion body disease. A possible residuum of an old herpesvirus infection. Acta Neuropathol. 10, 54–73 (1968).
Schuffler, M. D., Bird, T. D., Sumi, S. M. & Cook, A. A familial neuronal disease presenting as intestinal pseudoobstruction. Gastroenterology 75, 889–898 (1978).
Michaud, J. & Gilbert, J. J. Multiple system atrophy with neuronal intranuclear hyaline inclusions. Report of a new case with light and electron microscopic studies. Acta Neuropathol. (Berl.) 54, 113–119 (1981).
Munoz-Garcia, D. & Ludwin, S. K. Adult-onset neuronal intranuclear hyaline inclusion disease. Neurology 36, 785–790 (1986).
Oyer, C. E., Cortez, S., O’Shea, P. & Popovic, M. Cardiomyopathy and myocyte intranuclear inclusions in neuronal intranuclear inclusion disease: a case report. Hum. Pathol. 22, 722–724 (1991).
Takahashi-Fujigasaki, J. Neuronal intranuclear hyaline inclusion disease. Neuropathology 23, 351–359 (2003).
Sone, J. et al. Neuronal intranuclear hyaline inclusion disease showing motor-sensory and autonomic neuropathy. Neurology 65, 1538–1543 (2005).
Liu, Y. et al. Inclusion-positive cell types in adult-onset intranuclear inclusion body disease: implications for clinical diagnosis. Acta Neuropathol. 116, 615–623 (2008).
Sone, J. et al. Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology 76, 1372–1376 (2011).
Sone, J. et al. Neuronal intranuclear inclusion disease cases with leukoencephalopathy diagnosed via skin biopsy. J. Neurol. Neurosurg. Psychiatry 85, 354–356 (2014).
Sone, J. et al. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain 139, 3170–3186 (2016).
Sone, J. et al. Reply: Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor/ataxia syndrome: a morphological and molecular dilemma. Brain 140, e52 (2017).
Janota, I. Widespread intranuclear neuronal corpuscles (Marinesco bodies) associated with a familial spinal degeneration with cranial and peripheral nerve involvement. Neuropathol. Appl. Neurobiol. 5, 311–317 (1979).
Yamada, W. et al. Case of adult-onset neuronal intranuclear hyaline inclusion disease with negative electroretinogram. Doc. Ophthalmol. 134, 221–226 (2017).
Araki, K. et al. Memory loss and frontal cognitive dysfunction in a patient with adult-onset neuronal intranuclear inclusion disease. Intern. Med. 55, 2281–2284 (2016).
Kitagawa, N., Sone, J., Sobue, G., Kuroda, M. & Sakurai, M. Neuronal intranuclear inclusion disease presenting with resting tremor. Case Rep. Neurol. 6, 176–180 (2014).
Maddalena, A. et al. Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the standards and guidelines for clinical genetics laboratories of the american college of medical genetics. quality assurance subcommittee of the laboratory practice committee. Genet. Med. 3, 200–205 (2001).
Smith, K. R. et al. Reducing the exome search space for mendelian diseases using genetic linkage analysis of exome genotypes. Genome Biol. 12, R85 (2011).
Mitsuhashi, S. et al. Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads. Genome Biol. 20, 58 (2019).
Katoh, K., Misawa, K., Kuma, K. & Miyata, T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 30, 3059–3066 (2002).
Hamada, M., Ono, Y., Asai, K. & Frith, M. C. Training alignment parameters for arbitrary sequencers with LAST-TRAIN. Bioinformatics 33, 926–928 (2017).
Fiddes, I. T. et al. Human-specific NOTCH2NL genes affect notch signaling and cortical neurogenesis. Cell 173, 1356–1369 e22 (2018).
Suzuki, I. K. et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation. Cell 173, 1370–1384 e16 (2018).
Sedlazeck, F. J. et al. Accurate detection of complex structural variations using single-molecule sequencing. Nat. Methods 15, 461–468 (2018).
Dougherty, M. L. et al. Transcriptional fates of human-specific segmental duplications in brain. Genome Res. 28, 1566–1576 (2018).
Koike, H. et al. Nonmyelinating Schwann cell involvement with well-preserved unmyelinated axons in Charcot-Marie-Tooth disease type 1A. J. Neuropathol. Exp. Neurol. 66, 1027–1036 (2007).
Abecasis, G. R., Cherny, S. S., Cookson, W. O. & Cardon, L. R. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).
Jain, M. et al. Nanopore sequencing and assembly of a human genome with ultra-long reads. Nat. Biotechnol. 36, 338–345 (2018).
de Coster, W. et al. Structural variants identified by Oxford Nanopore PromethION sequencing of the human genome. Genome Res. https://doi.org/10.1101/gr.244939.118 (2019).
Frith, M. C. & Khan, S. A survey of localized sequence rearrangements in human DNA. Nucleic Acids Res. 46, 1661–1673 (2018).
O’Leary, N. A. et al. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 44, D733–D745 (2016).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
Iwama, K. et al. A novel SLC9A1 mutation causes cerebellar ataxia. J. Hum. Genet 63, 1049–1054 (2018).
Chen, J., Bardes, E. E., Aronow, B. J. & Jegga, A. G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 37, W305–W311 (2009).
Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5, e13984 (2010).
Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).
Sharp, A. J. et al. Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15. Genome Res. 20, 1271–1278 (2010).
The authors thank all of the patients and their families for participating in this study.
The authors also thank O. Komure, N. Kitagawa, H. Yoshimura, J. Ishii, K. Higashida, M. Togo, T. Yuasa, H. Nakayasu, Y. Suto, T. Manabe, M. Takahashi, M. Tsutiya, N. Uehara, H. Mori, T. Tokunaga, T. Inuzuka, A. Takekoshi, S. Anzai, K. Kondo, T. Takahashi, K. Muguruma, Y. Sugihara, K. Yokote, S. Takamura, N. Oohara, E. Hayano, K. Saiki, D. Hori, Y. Izumi, R. Kobayashi, M. Saiki, Y. Tsukahara, M. Kuriyama, T. Kurashige, Y. Takahashi, T. Noda, S. Takagi, K. Honda, H. Kishida, M. Ito, A. Yarita, Y. Satake, T. Inagaki, K. Hiraga, Y. Kato and many neurologists for clinical evaluation of patients with NIID and for providing support with the diagnosis of patients with NIID. This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18kk0205001, JP18ek0109348, JP18md0107059, JP18ek0109284, JP18dm020715, JP18dm0107059 and JP18am0101108; the Japan Society for the Promotion of Science (JSPS) KAKENHI grant numbers JP19659225, JP17K15639, JP17K16132, JP17K15630, JP17H06994, JP24591257, JP15K09312 and JP16K07464; MEXT Grant-in Aid Project under grant numbers 26119002 and 26117002; the Takeda Science Foundation; the Daiwa Securities Health Foundation; and the Termo Foundation for Life Sciences and Arts.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Journal of Human Genetics (2019)