Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia.
Frontotemporal lobar degeneration (FTLD) is a genetically heterogenous syndrome and has been associated most recently with a hexanucleotide repeat expansion within the C9ORF72 gene. Pathogenic TDP-43 gene (TARDBP) mutations have been identified in amyotrophic lateral sclerosis, but the role of TARDBP mutations in FTLD is more contradictory. To investigate the role of TARDBP mutations in a clinical series of Finnish FTLD patients, we sequenced TARDBP exons 1 to 6 in 77 FTLD patients. No evident pathogenic mutations were found. We identified a novel heterozygous c.876_878delCAG sequence variant in 2 related patients with behavioral variant frontotemporal dementia without amyotrophic lateral sclerosis. The variant is predicted to cause an amino acid deletion of serine at position 292 (p.Ser292del). However, p.Ser292del was also found in 1 healthy middle-aged control. Interestingly, both patients carried the C9ORF72 expansion. Therefore, the TARDBP variant p.Ser292del might be considered a rare polymorphism and the C9ORF72 repeat expansion the actual disease-causing mutation in the family. Our results suggest that TARDBP mutations are a rare cause of FTLD. However, the interaction of several genetic factors needs to be taken into account when investigating neurodegenerative diseases.
Departments of *Neurology ‡Ophthalmology, Institute of Clinical Medicine, University of Oulu †Clinical Research Center, Oulu University Hospital, Oulu, Finland §Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD ∥Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland ¶Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
Anna-Lotta
AL
Kaivorinne
Virpi
V
Moilanen
Marko
M
Kervinen
Alan E
AE
Renton
Bryan J
BJ
Traynor
Kari
K
Majamaa
Anne M
AM
Remes
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D015331:Cohort Studies; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D035781:Siblings
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins