Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes

Abstract

Objective: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. Methods: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. Results: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. Conclusion: PGRN mutations are not a common cause of ALS phenotypes.A myotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3-5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.1 Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.2 Approximately 5% of ALS patients have FTD (ALS-FTD) 3 and approximately half of patients with ''classical'' ALS have subtle frontal and temporal lobe cognitive impairment. 4 Many FTD cases similarly develop symptoms of motor neuron involvement during the course of their illness 5 and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy. 6 Recently, mutations in the progranulin (PGRN) gene have been described as the cause of ubiquitin positive FTD. 7 8 The overlap between ALS and FTD prompted us to screen 272 cases of sporadic ALS, 40 familial ALS cases and 49 patients diagnosed with ALS-FTD for mutations in this gene. METHODS SubjectsGenetic studies were approved by local research ethics committees (NIA IRB protocol #2003-081). Diagnosis of ALS was based on the El Escorial diagnostic criteria.9 Samples used are outlined in table 1. The samples from the Coriell NINDS DNA repository consisted of 45 Caucasian women and 89 Caucasian men, with an average age of symptom onset of 54.3 years (range 26-81). Of these, 34 (25.4%) had bulbar onset disease, 98 (73.1%) had limb onset weakness and the remaining 2 (1.5%) cases presented with respiratory symptoms. Three sporadic ALS patients were reported to have cognitive changes, but did not have a formal diagnosis of FTD or dementia.Of the 48 Irish cases, 20 were women and 28 were men. Average age of symptom onset was 58.9 years (range 29-79). Eight (16.7%) patients initially manifested symptoms in bulbar musculature, 38 (79.2%) cases reported limb onset symptoms and the site of onset was unspecified in the remaining 2 (4.1%) cases.Samples obtained from the brain banks at Johns Hopkins University, Columbia University and the University of Miami, consisted of 26 women and 40 men (missing data = 15), with an average onset of 65.5 years...

The granulin gene family: from cancer to dementia

“…Moreover, the ubiquitin/TDP-43 inclusions occur in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), where there is no strong link with GRN mutations. (66) Given the complex histopathological relationship between GRN mutations and ubiquitin/TDP-43 inclusions, are there any functional relationships between PGRN and TDP-43? The ubiquitin/TDP-43 inclusions do not contain PGRN, (67) and therefore the direct seeding of ubiquitin inclusions by PGRN is highly unlikely.…”

“…For instance, genetic variants of GRN may be disease modifiers in ALS, (76) although other investigators have not been able to reproduce this correlation. (66) PGRN has other functions in the brain. The male hypothalamus undergoes a default female developmental program until late in embryonic development when it is masculinized by the actions of circulating androgens.…”

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

“…Furthermore, other neurodegenerative brain diseases including corticobasal syndrome (CBS) [Masellis et al, 2006;Benussi et al, 2008;Rademakers et al, 2007;Le Ber et al, 2007;Lopez de Munain et al, 2008;Spina et al, 2007b;Le Ber et al, 2008], AD [van Duijn et al, 1994;Rademakers et al, 2002;Brouwers et al, 2007;Rademakers et al, 2007] and PD [Brouwers et al, 2007] were also linked with GRN mutations. However, compared to variants with unclear pathogenic significance, GRN null mutations were not frequently found in patients with a disease other than FTLD Schymick et al, 2007;Brouwers et al, 2007;Sleegers et al, in press;Pickering-Brown et al, 2008].…”

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

“…[17][18][19][20] In FTLD-ALS and ALS patients, the role of GRN is unclear because only missense variations with unclear pathogenicity have been detected. 21,22 In order to investigate the GRN-mutation frequency in FTLD patients recruited from an outpatient memory clinic in Stockholm, Sweden, we have sequenced GRN and measured serum-GRN levels.…”