Heterogeneity within a large kindred with frontotemporal dementia

Bruni, Amalia C.; Momeni, Parastoo; Bernardi, Livia; Tomaino, Carmine; Frangipane, Francesca; Elder, JT; Kawarai, Toshitaka; Sato, Christine; Pradella, Silvia; Wakutani, Yosuke; Anfossi, Maria; Gallo, Maura; Geracitano, Silvana; Costanzo, Angela; Smirne, Nicoletta; Curcio, Sabrina A.M.; Mirabelli, Maria; Puccio, Gianfranco; Colao, Rosanna; Maletta, Raffaele; Kertesz, Andrew; George-Hyslop, Peter St; Hardy, John; Rogaeva, Ekaterina

doi:10.1212/01.wnl.0000265220.64396.b4

Cited by 75 publications

(69 citation statements)

References 23 publications

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“…These higher frequencies can be explained by the presence of a strong founder effect of the Family DR8 founder mutation IVS115G4C in 8 out of 12 Belgian mutation carriers and the p.R493X mutation in 8 out of 39 U.S. mutation carriers, respectively . In addition, the number of studied patients was relatively low in some other studies [Huey et al, 2006;Bronner et al, 2007;Bruni et al, 2007]. Also, differences in patient recruitment methods, selection criteria, and geographical origin may account for the differences in mutation frequencies.…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 90%

“…Subsequently, GRN mutations were also identified in most of the other described FTLDU-17 families (Table 1). Families Dutch-III, Brescia-F071, Biv, and Seattle B segregated a frameshift mutation resulting in a PTC [Benussi et al, 2008;Bronner et al, 2007;Leverenz et al, 2007;Bruni et al, 2007]. In Family HDDD2, the disease was caused by a missense mutation (p.A9D) introducing a charged amino acid in the signal peptide, resulting in the mislocalization of the protein [Mukherjee et al, 2006[Mukherjee et al, , 2008, which was shown to lead to a decrease in secreted GRN protein [Mukherjee et al, 2008].…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

“…In Family HDDD2, the disease was caused by a missense mutation (p.A9D) introducing a charged amino acid in the signal peptide, resulting in the mislocalization of the protein [Mukherjee et al, 2006[Mukherjee et al, , 2008, which was shown to lead to a decrease in secreted GRN protein [Mukherjee et al, 2008]. In the Kertesz family, GRN mutations were excluded [Bruni et al, 2007]. The genetic cause of the disease in the Kertesz and Karolinska families [Froelich et al, 1997;Kertesz et al, 2000] is still unknown.…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

“…The loss of functional protein is mainly the result of loss of GRN transcript caused by NMD of transcripts containing PTCs (n 5 52) or by nuclear degradation of transcripts retaining the first intron due to splice-site mutations in intron 1 (n 5 2) Le Ber et al, 2007]. PTCs can be the result from nonsense mutations (n 5 12), splice-site mutations (n 5 10), and small insertions/deletions (n 5 30) Baker et al, 2006;Huey et al, 2006;Pickering-Brown et al, 2006Boeve et al, 2006;Masellis et al, 2006;Gass et al, 2006;Benussi et al, 2008;Bronner et al, 2007;Mesulam et al, 2007;Behrens et al, 2007;Leverenz et al, 2007;Bruni et al, 2007;Van Deerlin et al, 2007;Brouwers et al, 2007;Rademakers et al, 2007;Llado et al, 2007;Le Ber et al, 2007;Davion et al, 2007;Kelley et al, in press;Spina et al, 2007a;Mukherjee et al, 2008;Beck et al, 2008;Le Ber et al, 2008]. Second, loss of translation as a result of mutations affecting the Kozak sequence (n 5 4) Baker et al, 2006;Pickering-Brown et al, 2006;Boeve et al, 2006;Gass et al, 2006;Le Ber et al, 2008] and reduction of secreted protein due to missense mutations affecting the signal sequence (n 5 2) [Mukherjee et al, 2006;Gass et al, 2006;Kelley et al, in press;Mukherjee et al, 2008;Le Ber et al, 2008], results in reduced GRN.…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

“…Eight studies estimated the GRN mutation frequency in different FTLD series (Table 3) Baker et al, 2006;Huey et al, 2006;Gass et al, 2006;Bronner et al, 2007;Bruni et al, 2007;Le Ber et al, 2007Gijselinck 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).…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

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Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Communicated by Mark H. PaalmanMutations 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. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

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Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 90%

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

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Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Progranulin Mutations as Risk Factors for Alzheimer Disease

Perry¹,

Lehmann²,

Yokoyama³

et al. 2013

JAMA Neurol

120

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Importance: Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.Observations: This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. Conclusions and Relevance:In addition to autosomaldominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

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The Spectrum of Mutations in Progranulin

et al. 2010

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BACKGROUND: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. OBJECTIVES: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. DESIGN: Case-control study. SETTING: Clinical and neuropathology dementia research studies at 8 academic centers. PARTICIPANTS: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. MAIN OUTCOME MEASURES: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. RESULTS: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history. CONCLUSIONS: Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.

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Heterogeneity within a large kindred with frontotemporal dementia

Abstract: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

Cited by 75 publications

References 23 publications

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Progranulin Mutations as Risk Factors for Alzheimer Disease

The Spectrum of Mutations in Progranulin

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