Genetic origin of sporadic cases and RNA toxicity in neuronal intranuclear inclusion disease

Abstract

BackgroundGGC repeat expansion in NOTCH2NLC has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID.MethodsMultiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared.ResultsIn two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in NOTCH2NLC of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier.ConclusionOur study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

“…In order to explore whether or not patients carry pathogenic expansion in the NOTCH2NLC gene, we conducted a TP‐PCR as previously described 14 . TP‐PCR was performed in all individuals who were genetically negative in the above screening.…”

“…In order to explore whether or not patients carry pathogenic expansion in the NOTCH2NLC gene, we conducted a TP‐PCR as previously described. 14 TP‐PCR was performed in all individuals who were genetically negative in the above screening. To identify abnormal nucleotide repeat of all known SCA genes, we used 22‐FAM labeled primer sets for PCR, followed by capillary electrophoresis.…”

The polyG diseases: a new disease entity

“…Based on the relationship between phenotype and genotype, researchers divided familial genetically positive adult-onset NIID cases into three subgroups: parkinsonism-dominant NIID, muscle weakness-dominant NIID, and dementia-dominant NIID [ 110 ]. Nevertheless, several studies have indicated that carriers with more than 300 repeats of expanded CGG show a mild or asymptomatic phenotype [ 20 , 127 ]. Beyond NIID, expanded CGG repeats in NOTCH2NLC are occasionally related to a small proportion of Parkinson's disease (PD) [ 65 , 97 , 110 ], multiple system atrophy (MSA) [ 29 ], essential tremor (ET) [ 105 ], degenerative dementia [ 4 , 101 ], ALS [ 46 , 130 ], inherited peripheral neuropathy [ 118 ], distal motor neuropathy [ 122 , 128 ], mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) [ 57 , 123 ], and oculopharyngodistal myopathy (OPDM) [ 127 ].…”

“…Clinical and genetic anticipation are typical features in most STR-related diseases, while anticipation have not observed in patients with polyG diseases currently. Nucleotide repeat instability and unstable transmission of CGG repeats between parents and offspring have been reported in individual FXTAS, NIID, and OPDM families [ 5 , 20 ]. These characteristics suggest that polyG diseases may have different molecular genetic mechanisms compared to polyQ diseases.…”

“…Unexpectedly, males carrying large CGG repeat expansions (up to 300) in NOTCH2NLC seem to be asymptomatic, though NOTCH2NLC mRNA levels decrease as a consequence of hypermethylation around the CGG repeats, displaying a strikingly different prognosis in contrast to FXS patients with full mutation alleles of FMR1 [ 133 ]. However, these individuals may have children with NIID if the repeat number is contracted during spermatogenesis [ 20 ]. The inconsistent repeat number is related to genome instability, and possibly an explanation of variable disease phenotypes considering the length of polyG tracts translated by the repeats [ 66 ].…”