Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.
Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.
Memory Unit and Neuromuscular Diseases Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Oriol
O
Dols-Icardo
Alberto
A
García-Redondo
Ricard
R
Rojas-García
Raquel
R
Sánchez-Valle
Aina
A
Noguera
Estrella
E
Gómez-Tortosa
Pau
P
Pastor
Isabel
I
Hernández
Jesús
J
Esteban-Pérez
Marc
M
Suárez-Calvet
Sofía
S
Antón-Aguirre
Guillermo
G
Amer
Sara
S
Ortega-Cubero
Rafael
R
Blesa
Juan
J
Fortea
Daniel
D
Alcolea
Aura
A
Capdevila
Anna
A
Antonell
Albert
A
Lladó
José Luís
JL
Muñoz-Blanco
Jesús S
JS
Mora
Lucía
L
Galán-Dávila
Francisco Javier
FJ
Rodríguez De Rivera
Alberto
A
Lleó
Jordi
J
Clarimón
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015139:Blotting, Southern / Q000379:methods; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D014430:Twins, Monozygotic
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins