Progranulin mutations in Dutch familial frontotemporal lobar degeneration

VU University Amsterdam, Amsterdamo, North Holland, Netherlands
European Journal of HumanGenetics (Impact Factor: 4.35). 04/2007; 15(3):369-74. DOI: 10.1038/sj.ejhg.5201772
Source: PubMed


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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    • "PGRN has been shown to play a role in promoting neuronal survival, enhancing neurite outgrowth and regulating inflammation in the central nervous system (CNS) (Guo et al., 2010; Ryan et al., 2009; Tang et al., 2011; Van Damme et al., 2008; Xu et al., 2011). Interest in the regulation and function of PGRN in the brain has significantly increased following the discovery that mutations in the progranulin (also known as granulin) gene (GRN) are the major cause of autosomal dominant frontotemporal dementia (FTD) with tau-negative inclusions (Baker et al., 2006; Bronner et al., 2007; Cruts et al., 2006; Gass et al., 2006; Mukherjee et al., 2006; Pickering-Brown et al., 2006; van der Zee et al., 2007). "
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    ABSTRACT: The secreted growth factor progranulin (PGRN) has been shown to be important for regulating neuronal survival and outgrowth, as well as synapse formation and function. Mutations in the PGRN gene that result in PGRN haploinsufficiency have been identified as a major cause of frontotemporal dementia (FTD). Here we demonstrate that PGRN is colocalized with dense-core vesicle markers and is co-transported with brain-derived neurotrophic factor (BDNF) within axons and dendrites of cultured hippocampal neurons in both anterograde and retrograde directions. We also show that PGRN is secreted in an activity-dependent manner from synaptic and extrasynaptic sites, and that the temporal profiles of secretion are distinct in axons and dendrites. Neuronal activity is also shown to increase the recruitment of PGRN to synapses and to enhance the density of PGRN clusters along axons. Finally, treatment of neurons with recombinant PGRN is shown to increase synapse density, while decreasing the size of the presynaptic compartment and specifically the number of synaptic vesicles per synapse. Together, this indicates that activity-dependent secretion of PGRN can regulate synapse number and structure.
    Preview · Article · Sep 2013 · Journal of Cell Science
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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.
    Full-text · Article · May 2009 · Journal of Genetic Counseling
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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.
    Full-text · Article · Dec 2008 · Human Mutation
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