Human Disease Model Report: neuronal intranuclear inclusion disease

General Information

Name

neuronal intranuclear inclusion disease

FlyBase ID

FBhh0001477

Disease Ontology Term

neuronal intranuclear inclusion disease

Parent Disease

OMIM

NEURONAL INTRANUCLEAR INCLUSION DISEASE; NIID

Overview

This report describes neuronal intranuclear inclusion disease (NIID), a neuromuscular/neurodegenerative disease exhibiting autosomal dominant inheritance. The human gene implicated in this disease is NOTCH2NLC, which encodes one of three nearly identical, functional human NOTCH2-like genes. An expansion of CGG repeats in the 5' untranslated region of the NOTCH2NLC gene has been associatd with NIID. These repeats can be translated into a polyglycine-containing protein, uN2CpolyG, which forms protein inclusions and is toxic in cell models (Yu et al., 2022; pubmed:36191230; FBrf0254610). No ortholog of NOTCH2NLC has been identified in flies.

A UAS constructs of a small upstream open reading (ORF) in the 5'UTR of the Hsap\NOTCH2NLC gene has been introduced into flies; this construct, referred to as 'uN2C' includes an expanded poly-glycine repeat of 100 residues. Expression of the uN2CpolyG protein in the developing eye results in a neurodegeneration phenotype in the adult retina, while ubiquitous expression leads to intranuclear inclusion formation and progressive neurodegeneration in multiple systems.

[updated Oct. 2022 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: neuronal intranuclear inclusion disease

OMIM report

[NEURONAL INTRANUCLEAR INCLUSION DISEASE; NIID](https://omim.org/entry/603472)

Human gene(s) implicated

[NOTCH2 N-TERMINAL-LIKE C; NOTCH2NLC](https://omim.org/entry/618025)

Symptoms and phenotype

Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant, slowly progressive neurodegenerative disorder characterized by a wide range of clinical manifestations, including pyramidal and extrapyramidal symptoms, cerebellar ataxia, cognitive decline and dementia, peripheral neuropathy, and autonomic dysfunction. The age at onset varies, but most individuals present as adults between about 30 and 70 years of age. Brain imaging shows a characteristic leukoencephalopathy with high intensity signals in the corticomedullary junction on diffusion-weighted imaging, as well as white matter abnormalities in subcortical and brainstem regions (summary by Sone et al., 2016; pubmed:27797808). [from MIM:603472; 2022.10.26]

(OMIM, 2013-)

Genetics

Neuronal intranuclear inclusion disease is caused by a heterozygous repeat expansion (CGG) in the 5-prime untranslated region of the NOTCH2NLC gene on chromosome 1q21. [from MIM:603472; 2022.10.26]

(OMIM, 2013-)

Cellular phenotype and pathology

Pathologic investigation shows eosinophilic intranuclear inclusions in almost all cell types, including neurons, skin cells, fibroblasts, and skeletal muscle (Sone et al., 2016; pubmed:27797808). [from MIM:603472; 2022.10.26]

(OMIM, 2013-)

Molecular information

NOTCH2NLC encodes 1 of 3 nearly identical, functional human NOTCH2-like genes on chromosome 1q21. The NOTCH2L proteins appear to regulate Notch signaling and promote cortical neurogenesis (Suzuki et al., 2018; pubmed:29856955; Fiddes et al., 2018; pubmed:29856954). [from MIM:618025; 2022.10.26]

(OMIM, 2013-)

External links