Progranulin mutations in Dutch familial frontotemporal lobar degeneration

Department of Human Genetics, Section Medical Genomics, VU University Medical Center and VU University, Amsterdam, The Netherlands.
European Journal of HumanGenetics (Impact Factor: 4.23). 04/2007; 15(3):369-74. DOI: 10.1038/sj.ejhg.5201772
Source: PubMed

ABSTRACT Mutations in the progranulin (PGRN) gene have recently been identified in frontotemporal lobar degeneration with ubiquitin inclusions linked to chromosome 17q21. We report here the finding of two novel frameshift mutations and three possible pathogenic missense mutations in the PGRN gene. Furthermore, we determined the frequency of PGRN mutations in familial cases recruited from a large population-based study of frontotemporal lobar degeneration carried out in The Netherlands.

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Available from: Patrizia Rizzu, Mar 05, 2015
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    • "Five of these testees stated that resolving unbearable uncertainty with regard to carrying the mutation was an important motive for testing. Since then, despite the discovery of other pathogenic FTD genes (Bronner et al. 2007; Seelaar et al. 2008), a mere 13 additional individuals have been counseled for FTD in our center between 2003 and 2008. Furthermore, during this decade (1999–2008) we received only one request for prenatal diagnosis (PND) in 1999, and no requests for pre-implantation genetic diagnosis (PGD) for FTD. "
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    ABSTRACT: A decade of genetic counseling of frontotemporal dementia (FTD) affected families has generated two important observations. First, the uptake rate for presymptomatic testing for FTD is low in our department of Clinical Genetics at the Erasmus Medical Center in the Netherlands. Second, FTD at-risk counselees reported substantial familial opposition to genetic testing, which is distinct from the attitude in Huntington Disease affected families. We hypothesize that the low acceptance for FTD genetic counseling is consequential to the familial opposition and explain this within the theoretical framework of separation-individuation. Furthermore, we hypothesize that separation-individuation problems do not similarly influence the acceptance of HD genetic counseling, due to the educative role of the well-organised patient organization for HD in the Netherlands. We offer counseling recommendations that serve to facilitate the individuation of the counselee with respect to the FTD genetic test.
    Journal of Genetic Counseling 05/2009; 18(4):350-6. DOI:10.1007/s10897-009-9222-3 · 1.75 Impact Factor
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    • "Mutation frequencies. Eight studies estimated the GRN mutation frequency in different FTLD series (Table 3) [Cruts et al., 2006; Baker et al., 2006; Huey et al., 2006; Gass et al., 2006; Bronner et al., 2007; Bruni et al., 2007; Le Ber et al., 2007, 2008; Gijselinck et al., 2008; Pickering-Brown et al., 2008]. The mutation frequencies differed greatly between the different studies ranging from 1.3 to 11.7% in the total group of patients and from 3.4 to 25.6% when only familial patients were considered (Table 3). "
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    ABSTRACT: Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified.
    Human Mutation 12/2008; 29(12):1373-86. DOI:10.1002/humu.20785 · 5.05 Impact Factor
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    • "Our study gives a more accurate evaluation of the frequency in a large unselected population of patients with fvFTD, with separate evaluation of FTD-MND. The frequency of GRN mutations in familial forms in our study is close to that evaluated by Huey and his collaborators (2006), but higher than in two smaller Dutch (4%) and Italian populations (1%) (Bruni et al., 2007; Bronner et al., 2007). These discrepancies may reflect geographical differences or may be due to different criteria for familial disease and variable proportions of patients with FTD-MND, not caused by GRN mutations, included in the different studies. "
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    ABSTRACT: Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.
    Brain 04/2008; 131(Pt 3):732-46. DOI:10.1093/brain/awn012 · 10.23 Impact Factor
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