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NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation
  1. Yu Fan1,2,
  2. Yuming Xu1,3,4,
  3. Changhe Shi1,3,4
  1. 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  2. 2Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  3. 3Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  4. 4Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  1. Correspondence to Dr Changhe Shi, Department of Neurology, Zhengzhou University First Affiliated Hospital, Zhengzhou, China; shichanghe{at}gmail.com

Abstract

GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC is the most common causative factor in neuronal intranuclear inclusion disease (NIID) in Asians. Such expanded GGC repeats have been identified in patients with leukoencephalopathy, essential tremor (ET), multiple system atrophy, Parkinson’s disease (PD), amyotrophic lateral sclerosis and oculopharyngodistal myopathy (OPDM). Herein, we review the recently reported NOTCH2NLC-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be NOTCH2NLC-specific and should be investigated in other patients with NOTCH2NLC mutations. NOTCH2NLC GGC repeat expansion was rarely identified in patients of European ancestry, whereas the actual prevalence of the expansion in European patients may be potentially higher than reported, and the CGG repeats in LRP12/GIPC1 are suggested to be screened in European patients with NIID. The repeat size and interruptions in NOTCH2NLC GGC expansion confer pleiotropic effects on clinical phenotype, a pure and stable ET phenotype may be an early symptom of NIID, and GGC repeats in NOTCH2NLC possibly give rise to ET. An association may also exist between intermediate-length NOTCH2NLC GGC repeat expansion and patients affected by PD and ET. NOTCH2NLC-OPDM highly resembles NOTCH2NLC-NIID, the two disorders may be the variations of a single neurodegenerative disease, and there may be a disease-causing upper limit in size of GGC repeats in NOTCH2NLC, repeats over which may be non-pathogenic. The haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.

  • genetics
  • genotype
  • phenotype
  • DNA repeat expansion

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Footnotes

  • Contributors CS and YX had the idea for the article, YF and CS performed the literature search and data analysis, YF drafted and critically revised the work.

  • Funding This work was supported by the National Natural Science Foundation of China to CS (grant number 81974211, 81771290), National Key R&D Program of China to YX (2017YFA0105000) and the National Natural Science Foundation of China to YX (grant numbers U1904207, 81530037, 91849115).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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