title: Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD.
abstract: A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found.
authors.affiliation: Department of Pharmacology and Clinical Neuroscience.
authors.forename: Angelica
authors.initials: A
authors.lastname: Nordin
authors.affiliation: Department of Pharmacology and Clinical Neuroscience Division of Neurology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Akimoto
authors.affiliation: Department of Chemistry Computational Life Science Cluster (CLIC) and.
authors.forename: Anna
authors.initials: A
authors.lastname: Wuolikainen
authors.affiliation: Department of Pharmacology and Clinical Neuroscience.
authors.forename: Helena
authors.initials: H
authors.lastname: Alstermark
authors.affiliation: Department of Chemistry Computational Life Science Cluster (CLIC) and.
authors.forename: Pär
authors.initials: P
authors.lastname: Jonsson
authors.affiliation: Department of Pharmacology and Clinical Neuroscience.
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå SE-90187, Sweden and.
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå SE-90187, Sweden and.
authors.forename: Karin S
authors.initials: KS
authors.lastname: Graffmo
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå SE-90187, Sweden and.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå SE-90187, Sweden and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brännström
authors.affiliation: Department of Pharmacology and Clinical Neuroscience peter.andersen@umu.se.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
mesh_terms: D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000473:pathology; D018450:Disease Progression; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D010296:Parietal Lobe / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D020080:Tandem Repeat Sequences
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins