Bart Dermaut

Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.

Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.

Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.

Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase γ (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.

Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple large-scale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population.

A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques

Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule‐associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy‐related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick‐type tauopathy in the absence of extracellular β‐amyloid deposits. The mutation is predicted to substitute Gly→Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical‐genetic investigation showed a positive family history of FTD‐like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick‐type tauopathy without MAPT mutations.

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer’s disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects.

Objective: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. Methods: APOE genotyping was performed in patients with probable Alzheimer’s disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson’s disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). Results: The APOE allele frequencies of this Belgian control population (ε2: 6.9%; ε3: 76.2%; ε4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE ε4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE ε3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE ε2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE ε4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of ε4 alleles in MCI and mixed dementia patients. Conclusions: This study confirmed the risk association between APOE ε4 and AD. The observation that APOE ε4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE ε4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.

Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.

Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations.

Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS.

The nuclear TAR DNA binding protein (TDP-43) is deposited in ubiquitin-positive inclusions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two clinicopathologically overlapping neurodegenerative diseases. In this study we excluded mutations and copy number variations in the gene encoding TDP-43 (TARDBP) from an extended series of 173 FTD and 237 ALS patients. Further, we did not identify association of common genetic variants in these patients. Our data implicate that TDP-43 has no primary genetic role in the pathophysiological mechanisms underlying central nervous system neurodegeneration in these diseases.

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.

We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53–79 years). In this family we previously excluded the known Alzheimers disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9–13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5′ regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.

Octapeptide repeat insertions in the prion protein gene and early onset dementia

Objectives: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer’s disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. Methods: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. Results: We found an increasing number of repeats associated with younger age at onset (p<0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p<0.001) when adjusting for age at onset. Conclusions: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.