A family with neuronal intranuclear inclusion disease with focal segmental glomerulosclerosis.
Focal segmental glomerulosclerosis
Hypermethylation
Nanopore long-read sequencing
Neuronal intranuclear inclusion disease
Thalamus
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
30 Jul 2024
30 Jul 2024
Historique:
received:
13
05
2024
accepted:
18
07
2024
revised:
17
07
2024
medline:
30
7
2024
pubmed:
30
7
2024
entrez:
30
7
2024
Statut:
aheadofprint
Résumé
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events. Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis. ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case. This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.
Sections du résumé
BACKGROUND
BACKGROUND
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events.
METHODS
METHODS
Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis.
RESULTS
RESULTS
ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case.
CONCLUSIONS
CONCLUSIONS
This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.
Identifiants
pubmed: 39078482
doi: 10.1007/s00415-024-12593-w
pii: 10.1007/s00415-024-12593-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP23K14750
Organisme : Japan Society for the Promotion of Science
ID : JP23H02829
Organisme : Japan Research Promotion Society for Cardiovascular Diseases
ID : JP21K07869
Organisme : Japan Agency for Medical Research and Development
ID : JP23ek0109674
Organisme : Japan Agency for Medical Research and Development
ID : JP23ek0109617
Organisme : Japan Agency for Medical Research and Development
ID : JP23ek0109549
Organisme : Japan Agency for Medical Research and Development
ID : JP23ek0109549
Informations de copyright
© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S et al (2016) Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain 139:3170–3186
doi: 10.1093/brain/aww249
pubmed: 27797808
pmcid: 5382941
Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K et al (2019) Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet 51:1215–1221
doi: 10.1038/s41588-019-0459-y
pubmed: 31332381
Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K et al (2019) Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet 51:1222–1232
doi: 10.1038/s41588-019-0458-z
pubmed: 31332380
Ogasawara M, Iida A, Kumutpongpanich T, Ozaki A, Oya Y, Konishi H et al (2020) CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations. Acta Neuropathol Commun 8:204
doi: 10.1186/s40478-020-01084-4
pubmed: 33239111
pmcid: 7690190
Yu J, Deng J, Guo X, Shan J, Luan X, Cao L et al (2021) The GGC repeat expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy type 3. Brain 144:1819–1832
doi: 10.1093/brain/awab077
pubmed: 33693509
pmcid: 8320266
Liu Y, Li H, Liu X, Wang B, Yang H, Wan B et al (2022) Clinical and mechanism advances of neuronal intranuclear inclusion disease. Front Aging Neurosci 14:934725
doi: 10.3389/fnagi.2022.934725
pubmed: 36177481
pmcid: 9513122
Sone J, Tanaka F, Koike H, Inukai A, Katsuno M, Yoshida M et al (2011) Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology 76:1372–1376
doi: 10.1212/WNL.0b013e3182166e13
pubmed: 21411744
Sone J, Kitagawa N, Sugawara E, Iguchi M, Nakamura R, Koike H et al (2014) Neuronal intranuclear inclusion disease cases with leukoencephalopathy diagnosed via skin biopsy. J Neurol Neurosurg Psychiatry 85:354–356
doi: 10.1136/jnnp-2013-306084
pubmed: 24039026
Hayashi T, Katagiri S, Mizobuchi K, Yoshitake K, Kameya S, Matsuura T et al (2020) Heterozygous GGC repeat expansion of NOTCH2NLC in a patient with neuronal intranuclear inclusion disease and progressive retinal dystrophy. Ophthalmic Genet 41:93–95
doi: 10.1080/13816810.2020.1723119
pubmed: 32039647
Chen H, Lu L, Wang B, Cui G, Wang X, Wang Y et al (2020) Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion disease. Ann Clin Transl Neurol 7:1930–1941
doi: 10.1002/acn3.51189
pubmed: 32931652
pmcid: 7545592
Human Genetic Variation Database. http://www.hgvd.genome.med.kyoto-u.ac.jp/ . Accessed 12 May 2024
jMorp. https://jmorp.megabank.tohoku.ac.jp/ . Accessed 12 May 2024
gnomAD. https://gnomad.broadinstitute.org/ . Accessed 12 May 2024
MITOMAP. https://www.mitomap.org/MITOMAP . Accessed 27 June 2024
Utsuno Y, Hamada K, Hamanaka K, Miyoshi K, Tsuchimoto K, Sunada S et al (2024) Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders. J Hum Genet 69:69–77
doi: 10.1038/s10038-023-01206-5
pubmed: 38012394
Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814
doi: 10.1093/nar/gkg509
pubmed: 12824425
pmcid: 168916
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
doi: 10.1038/nmeth0410-248
pubmed: 20354512
pmcid: 2855889
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362
doi: 10.1038/nmeth.2890
pubmed: 24681721
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315
doi: 10.1038/ng.2892
pubmed: 24487276
pmcid: 3992975
Fukuda H, Yamaguchi D, Nyquist K, Yabuki Y, Miyatake S, Uchiyama Y et al (2021) Father-to-offspring transmission of extremely long NOTCH2NLC repeat expansions with contractions: genetic and epigenetic profiling with long-read sequencing. Clin Epigenetics 13:204
doi: 10.1186/s13148-021-01192-5
pubmed: 34774111
pmcid: 8590777
Deng J, Zhou B, Yu J, Han X, Fu J, Li X et al (2022) Genetic origin of sporadic cases and RNA toxicity in neuronal intranuclear inclusion disease. J Med Genet 59:462–469
doi: 10.1136/jmedgenet-2020-107649
pubmed: 33766934
Horino T, Matsumoto T, Inoue K, Ichii O, Terada Y (2018) A case of neuronal intranuclear inclusion disease associated with lupus nephritis-like nephropathy. eNeurologicalSci 10:28–30
doi: 10.1016/j.ensci.2018.01.002
pubmed: 29430526
pmcid: 5790813
Motoki M, Nakajima H, Sato T, Tada M, Kakita A, Arawaka S (2018) Neuronal intranuclear inclusion disease showing intranuclear inclusions in renal biopsy 12 years earlier. Neurology 91:884–886
doi: 10.1212/WNL.0000000000006480
pubmed: 30282768
Ji G, Zhao Y, Zhang J, Dong H, Wu H, Chen X et al (2022) NOTCH2NLC-related oculopharyngodistal myopathy type 3 complicated with focal segmental glomerular sclerosis: a case report. BMC Neurol 22:243
doi: 10.1186/s12883-022-02766-3
pubmed: 35788208
pmcid: 9251914
Morita K, Shinzato T, Endo Y, Suzuki M, Yoshida H, Sone J et al (2023) A case of unusual renal manifestation in a patient with neuronal intranuclear inclusion disease treated with steroids. Clin Case Rep 11:e7730
doi: 10.1002/ccr3.7730
pubmed: 37564608
pmcid: 10410123
Shabaka A, Tato Ribera A, Fernández-Juárez G (2020) Focal segmental glomerulosclerosis: state-of-the-art and clinical perspective. Nephron 144:413–427
doi: 10.1159/000508099
pubmed: 32721952
Tai H, Wang A, Zhang Y, Liu S, Pan Y, Li K et al (2023) Clinical features and classification of neuronal intranuclear inclusion disease. Neurol Genet 9:e200057
doi: 10.1212/NXG.0000000000200057
pubmed: 37090934
pmcid: 10117695
Guo X, Wang Z, Li F (2022) Diffuse cortical injury and basal ganglia high signals on diffusion-weighted imaging in neuronal intranuclear inclusion disease. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2022.2970
doi: 10.1001/jamaneurol.2022.2970
pubmed: 36190705
Ishihara T, Okamoto T, Saida K, Saitoh Y, Oda S, Sano T et al (2020) Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy. Neurol Genet 6:e531
doi: 10.1212/NXG.0000000000000531
pubmed: 33324757
pmcid: 7713717
Birtel J, von Landenberg C, Gliem M, Gliem C, Reimann J, Kunz WS et al (2022) Mitochondrial retinopathy. Ophthalmol Retina 6:65–79
doi: 10.1016/j.oret.2021.02.017
pubmed: 34257060
Imasawa T, Hirano D, Nozu K, Kitamura H, Hattori M, Sugiyama H et al (2022) Clinicopathologic features of mitochondrial nephropathy. Kidney Int Rep 7:580–590
doi: 10.1016/j.ekir.2021.12.028
pubmed: 35257070
pmcid: 8897298
Tian Y, Zhou L, Gao J, Jiao B, Zhang S, Xiao Q et al (2022) Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease. J Neurol Neurosurg Psychiatry 93:1289–1298
doi: 10.1136/jnnp-2022-329772
pubmed: 36150844
Yu J, Liufu T, Zheng Y, Xu J, Meng L, Zhang W et al (2022) CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model. Proc Natl Acad Sci U S A 119:e2208649119
doi: 10.1073/pnas.2208649119
pubmed: 36191230
pmcid: 9565157
Liu Q, Zhang K, Kang Y, Li Y, Deng P, Li Y et al (2022) Expression of expanded GGC repeats within NOTCH2NLC causes behavioral deficits and neurodegeneration in a mouse model of neuronal intranuclear inclusion disease. Sci Adv 8:eadd6391
doi: 10.1126/sciadv.add6391
pubmed: 36417528
pmcid: 9683706
Sun QY, Xu Q, Tian Y, Hu ZM, Qin LX, Yang JX et al (2020) Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor. Brain 143:222–233
doi: 10.1093/brain/awz372
pubmed: 31819945