Neuronal intranuclear inclusion disease is genetically heterogeneous

Chen, Zhongbo; Yau, Wai Yan; Jaunmuktane, Zane; Tucci, Arianna; Sivakumar, Prasanth; Taliun, Sarah A. Gagliano; Turner, Chris; Efthymiou, Stéphanie; Ibáñez, Kristina; Sullivan, Roisin; Bibi, Farah; Athanasiou-Fragkouli, Alkyoni; Bourinaris, Thomas; Zhang, David; Révész, Tamás; Lashley, Tammaryn; DeTure, Michael; Dickson, Dennis W.; Josephs, Keith A.; Gelpí, Ellen; Kovács, Gábor G.; Halliday, Glenda M.; Rowe, Dominic B.; Blair, Ian P.; Tienari, Pentti J.; Suomalainen, Anu; Fox, Nick C.; Wood, Nicholas W.; Lees, Andrew J.; Haltia, Matti; Hardy, John; Ryten, Mina; Vandrovcová, Jana; Houlden, Henry

doi:10.1002/acn3.51151

Cited by 42 publications

(54 citation statements)

References 18 publications

(39 reference statements)

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“…During this analysis, we noted that various European individuals with NIID with typical p62-positive intranuclear inclusions were nevertheless negative for uN2CpolyG staining ( Figure S2 H; data are summarized in Table S1 ). Genetic analyses revealed that these individuals are negative for the NOTCH2NLC GGC expansion, which is consistent with a recent report showing that most Europeans with NIID are negative for this mutation ( Chen et al., 2020b ). These unexpected results suggest that NIID is a heterogenous syndrome and that other mutations causing subtypes of this disorder remain to be identified, notably in European individuals with NIID.…”

Section: Resultssupporting

confidence: 91%

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

Boivin¹,

Deng²,

Pfister³

et al. 2021

Neuron

116

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Summary Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5′ UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.

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Section: Resultssupporting

confidence: 91%

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

Boivin¹,

Deng²,

Pfister³

et al. 2021

Neuron

116

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“…We concede that our study and algorithm predominantly focused on juvenile and adult-onset NIID, partly due to the rarity of reported iNIID. 4 The report of the European infant with iNIID who was also tested negative for the NOTCH2NLC GGC repeat expansion strengthens our proposal that NIID is a genetically heterogeneous disease. 5 NIID patients of European descent likely carry the same trinucleotide repeat at a different genetic locus, analogous to the recent discovery of a pentanucleotide expansion in six different genetic loci responsible for benign adult familial myoclonic epilepsy in different ethnic populations.…”

supporting

confidence: 73%

“…We concede that our study and algorithm predominantly focused on juvenile and adult‐onset NIID, partly due to the rarity of reported iNIID 4 . The report of the European infant with iNIID who was also tested negative for the NOTCH2NLC GGC repeat expansion strengthens our proposal that NIID is a genetically heterogeneous disease 5 .…”

Section: Figurementioning

confidence: 52%

Reply: Genetic heterogeneity of neuronal intranuclear inclusion disease. What about the infantile variant?

Yau

Chen

Sullivan

et al. 2021

Ann Clin Transl Neurol

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“…In 2020, a new European study reported that no abnormal NOTCH2NLC GGC expansion was found in 11 NIID patients confirmed by autopsy, but none of these patients underwent skin biopsy ( 16 ). In this study, the number of GGC repeats of NOTCH2NLC gene in one patient with positive skin biopsy was 58, which met the standard of intermediate-length repeat expansions reported by us ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

The Value of NOTCH2NLC Gene Detection and Skin Biopsy in the Diagnosis of Neuronal Intranuclear Inclusion Disease

et al. 2021

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The clinical manifestations of neuronal intranuclear inclusion disease (NIID) are heterogeneous, and the premortem diagnosis is mainly based on skin biopsy findings. Abnormal GGC repeat expansions in NOTCH2NLC was recently identified in familial and sporadic NIID. The comparison of diagnostic value between abnormal GGC repeat expansions of NOTCH2NLC and skin biopsy has not been conducted yet. In this study, skin biopsy was performed in 10 suspected adult NIID patients with clinical and imaging manifestations, and GGC repeat size in NOTCH2NLC was also screened by repeat primed-PCR and GC-rich PCR. We found that five cases had ubiquitin-immunolabelling intranuclear inclusion bodies by skin biopsy, and all of them were identified with abnormal GGC repeat expansions in NOTCH2NLC, among whom four patients showed typical linear hyperintensity at corticomedullary junction on DWI. Five (5/10) NIID patients were diagnosed by combination of NOTCH2NLC gene detection, skin biopsy or combination of NOTCH2NLC, and typical MRI findings. The diagnostic performance of NOTCH2NLC gene detection was highly consistent with that of skin biopsy (Kappa = 1). The unexplained headache was firstly reported as a new early phenotype of NIID. These findings indicate that NOTCH2NLC gene detection is needed to be a supplement in the diagnose flow of NIID and also may be used as an alternative method to skin biopsy especially in Asian population.

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Neuronal intranuclear inclusion disease is genetically heterogeneous

Cited by 42 publications

References 18 publications

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

Reply: Genetic heterogeneity of neuronal intranuclear inclusion disease. What about the infantile variant?

The Value of NOTCH2NLC Gene Detection and Skin Biopsy in the Diagnosis of Neuronal Intranuclear Inclusion Disease

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