Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression

Philip McGoldrick, Ming Zhang, Marka van Blitterswijk, Christine Sato, Danielle Moreno, Shangxi Xiao, Ashley B. Zhang, Paul M. McKeever, Anna Weichert, Raphael Schneider, Julia Keith, Leonard Petrucelli, Rosa V Rademakers, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.

Original languageEnglish (US)
Pages (from-to)e323-e331
JournalNeurology
Volume90
Issue number4
DOIs
StatePublished - Jan 23 2018

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Dipeptides
Amyotrophic Lateral Sclerosis
Fathers
RNA
Pathology
Proteins
Nuclear Family
Alleles
Frontotemporal Lobar Degeneration
Haploinsufficiency
Mosaicism
Molecular Pathology
Southern Blotting
Cerebellum
Up-Regulation
Parents
Messenger RNA
DNA

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

McGoldrick, P., Zhang, M., van Blitterswijk, M., Sato, C., Moreno, D., Xiao, S., ... Rogaeva, E. (2018). Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression. Neurology, 90(4), e323-e331. https://doi.org/10.1212/WNL.0000000000004865

Unaffected mosaic C9orf72 case : RNA foci, dipeptide proteins, but upregulated C9orf72 expression. / McGoldrick, Philip; Zhang, Ming; van Blitterswijk, Marka; Sato, Christine; Moreno, Danielle; Xiao, Shangxi; Zhang, Ashley B.; McKeever, Paul M.; Weichert, Anna; Schneider, Raphael; Keith, Julia; Petrucelli, Leonard; Rademakers, Rosa V; Zinman, Lorne; Robertson, Janice; Rogaeva, Ekaterina.

In: Neurology, Vol. 90, No. 4, 23.01.2018, p. e323-e331.

Research output: Contribution to journalArticle

McGoldrick, P, Zhang, M, van Blitterswijk, M, Sato, C, Moreno, D, Xiao, S, Zhang, AB, McKeever, PM, Weichert, A, Schneider, R, Keith, J, Petrucelli, L, Rademakers, RV, Zinman, L, Robertson, J & Rogaeva, E 2018, 'Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression', Neurology, vol. 90, no. 4, pp. e323-e331. https://doi.org/10.1212/WNL.0000000000004865
McGoldrick P, Zhang M, van Blitterswijk M, Sato C, Moreno D, Xiao S et al. Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression. Neurology. 2018 Jan 23;90(4):e323-e331. https://doi.org/10.1212/WNL.0000000000004865
McGoldrick, Philip ; Zhang, Ming ; van Blitterswijk, Marka ; Sato, Christine ; Moreno, Danielle ; Xiao, Shangxi ; Zhang, Ashley B. ; McKeever, Paul M. ; Weichert, Anna ; Schneider, Raphael ; Keith, Julia ; Petrucelli, Leonard ; Rademakers, Rosa V ; Zinman, Lorne ; Robertson, Janice ; Rogaeva, Ekaterina. / Unaffected mosaic C9orf72 case : RNA foci, dipeptide proteins, but upregulated C9orf72 expression. In: Neurology. 2018 ; Vol. 90, No. 4. pp. e323-e331.
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abstract = "OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21{\%} among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.",
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T2 - RNA foci, dipeptide proteins, but upregulated C9orf72 expression

AU - McGoldrick, Philip

AU - Zhang, Ming

AU - van Blitterswijk, Marka

AU - Sato, Christine

AU - Moreno, Danielle

AU - Xiao, Shangxi

AU - Zhang, Ashley B.

AU - McKeever, Paul M.

AU - Weichert, Anna

AU - Schneider, Raphael

AU - Keith, Julia

AU - Petrucelli, Leonard

AU - Rademakers, Rosa V

AU - Zinman, Lorne

AU - Robertson, Janice

AU - Rogaeva, Ekaterina

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N2 - OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.

AB - OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.

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