Dataset Information

Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia.

ABSTRACT: 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.

SUBMITTER: Kaivorinne AL

PROVIDER: S-EPMC3511614 | biostudies-literature | 2014 Apr-Jun

REPOSITORIES: biostudies-literature

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Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia.

Kaivorinne Anna-Lotta AL Moilanen Virpi V Kervinen Marko M Renton Alan E AE Traynor Bryan J BJ Majamaa Kari K Remes Anne M AM

Alzheimer disease and associated disorders 20140401 2

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 p ...[more]

PMID: 22892647

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Project description:Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

Project description:Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

Dataset Information

Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia.

Publications

Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia.

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