Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

Nat Genet. 2019 Aug;51(8):1222-1232. doi: 10.1038/s41588-019-0458-z. Epub 2019 Jul 22.

Abstract

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ataxia / genetics*
  • Ataxia / pathology
  • Brain / metabolism
  • Brain / pathology*
  • Case-Control Studies
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / pathology
  • Genetic Markers*
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Intranuclear Inclusion Bodies / genetics
  • Intranuclear Inclusion Bodies / pathology
  • Linkage Disequilibrium
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Male
  • Middle Aged
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / pathology
  • Mutation
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / pathology
  • Neuroimaging / methods
  • Pedigree
  • Tremor / genetics*
  • Tremor / pathology
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • FMR1 protein, human
  • Genetic Markers
  • LRP12 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Fragile X Mental Retardation Protein

Supplementary concepts

  • Fragile X Tremor Ataxia Syndrome
  • Neuronal intranuclear inclusion disease
  • Oculopharyngodistal Myopathy