Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis

By M. Dejesus‐Hernandez, I. Mackenzie, Brad Boeve, A. Boxer, M. Baker, Nicola J. Rutherford, Alexandra M. Nicholson, N. Finch, H. F. Gilmer, J. Adamson and 18 more. Neuron, 2011

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SUMMARY Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/a14363772a9926a299f67b9fdebfb404d9b6100d

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Citations in the corpus

Amyotrophic lateral sclerosis (2022, background): “Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2.”
Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. (2013, positive): “The accumulation of RNA transcripts containing the GGGGCC repeat within nuclear foci in frontal cortex and spinal cord in c9FTD/ALS also suggests a toxic RNA gain of function (DeJesus-Hernandez et al., 2011).”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, neutral): “, 2009), C9ORF72 (Hexanucleotide repeat expansion in C9ORF72) (Dejesus-Hernandez et al., 2011; Renton et al., 2011), ATXN2 (Ataxin-2) (Elden et al.”
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “304,335 The mechanism by which these repeat expansions may cause disease is outlined in three hypotheses: ﬁ rst, downregulation of gene expression (haploinsuf ﬁ ciency) leads to a loss of C9orf72 ’ s normal cellular function; second, the presence of sense and antisense RNA foci could sequester…”
Amyotrophic lateral sclerosis: a clinical review (2020, background): “In 2011, C9orf72 was discovered, responsible for 30%–50% of fALS and for 7%–10% of sALS [26,27].”
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD (2011, background): “We favor the second as a mechanism in chromosome 9 FTD/ALS, given the large size of the expansion visualized by FISH and its noncoding localization within the C9ORF72 gene.”
Liquid-Liquid Phase Separation in Disease. (2019, background): “, HD, and other (CAG)n expansion disorders, or the most common genetic form of ALS/FTD linked to a (GGGGCC)n expansion in the C9ORF72 gene (42, 131), further exemplify aberrant phase separation linked to neurodegeneration.”