MAPT Mutation Carriers Research Articles

C5 Molecular Genetics of frontotemporal lobar neurodegeneration

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically and genetically highly complex disorder. Up to 50% of FTLD patients have a positive family history of dementia and in the majority of these families the disease is inherited as an autosomal dominant trait. Mutations have been identified in the microtubule associated protein tau ( MAPT, 17q21.1), the progranulin (PGRN, 17q21.31), and more rarely in the charged multivesicular body protein 2B ( CHMP2B, 3p11.2) and the valosin containing protein ( VCP, 9p13.3) genes. In VCP carriers the disease is associated with inclusion body myopathy, Paget disease of the bone, and frontotemporal lobar degeneration (FTLD), referred to as IBMPFD. FTLD patients are characterized by progressive deterioration in behavior, personality and language with initial relative preservation of memory. In addition, FTLD patients may develop movement abnormalities such as parkinsonism and motor neuron disease. At autopsy MAPT mutation carriers consistently show tau pathology. In contrast, mutations in PGRN, CHMP2B and VCP lead to FTD with ubiquitin-immunoreactive (ub-ir) inclusions (FTDU) with as main component the TAR-DNA-binding protein (TDP-43). Mutations were not identified in the TARDBP gene at 1p36 in FTLD patients but in amyotrophic lateral sclerosis (ALS) patients. The similar ub-ir pathology suggests that these genes may be connected trough a common disease pathway leading to neurodegeneration and the formation of these pathognomic inclusions. However, functional data has not yet been able to provide evidence for a direct biological between both.

Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations

Two hundred and twenty-three consecutive patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration (FTLD), and 259 patients with motor neuron disease (MND), for whom genomic DNA was available, were investigated for the presence of mutations in tau (MAPT) and progranulin (PGRN) genes. All FTLD patients had undergone longitudinal neuropsychological and clinical assessment, and in 44 cases, the diagnosis had been pathologically confirmed at post-mortem. Six different PGRN mutations were found in 13 (6%) patients with FTLD. Four apparently unrelated patients shared exon Q415X 10 stop codon mutation. However, genotyping data revealed all four patients shared common alleles of 15 SNPs from rs708386 to rs5848, defining a 45.8-kb haplotype containing the whole PGRN gene, suggesting they are related. Three patients shared exon 11 R493X stop codon mutation. Four patients shared exon 10 V452WfsX38 frameshift mutation. Two of these patients were siblings, though not apparently related to the other patients who in turn appeared unrelated. One patient had exon 1 C31LfsX34 frameshift mutation, one had exon 4 Q130SfsX130 frameshift mutation and one had exon 10 Q468X stop codon mutation. In addition, two non-synonymous changes were detected: G168S change in exon 5 was found in a single patient, with no family history, who showed a mixed FTLD/MND picture and A324T change in exon 9 was found in two cases; one case of frontotemporal dementia (FTD) with a sister with FTD+MND and the other in a case of progressive non-fluent aphasia (PNFA) without any apparent family history. MAPT mutations were found in 17 (8%) patients. One patient bore exon 10 + 13 splice mutation, and 16 patients bore exon 10 + 16 splice mutation. When PGRN and MAPT mutation carriers were excluded, there were no significant differences in either the allele or genotype frequencies, or haplotype frequencies, between the FTLD cohort as a whole, or for any clinical diagnostic FTLD subgroup, and 286 controls or between MND cases and controls. However, possession of the A allele of SNP rs9897526, in intron 4 of PGRN, delayed mean age at onset by approximately 4 years. Patients with PGRN and MAPT mutations did not differ significantly from other FTLD cases in terms of gender distribution or total duration of illness. However, a family history of dementia in a first-degree relative was invariably present in MAPT cases, but not always so in PGRN cases. Onset of illness was earlier in MAPT cases compared to PGRN and other FTLD cases. PNFA, combined with limb apraxia was significantly more common in PGRN mutation cases than other FTLD cases. By contrast, the behavioural disorder of FTD combined with semantic impairment was a strong predictor of MAPT mutations. These findings complement recent clinico-pathological findings in suggesting identifiable associations between clinical phenotype and genotype in FTLD.