Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features

Karch, Celeste M.; Ezerskiy, Lubov; Redaelli, Veronica; Giovagnoli, Anna Rita; Tiraboschi, Pietro; Pelliccioni, Giuseppe; Pelliccioni, Paolo; Kapetis, Dimos; D’Amato, Ilaria; Piccoli, Elena; Ferretti, Maria Giulia; Tagliavini, Fabrizio; Rossi, Giacomina

doi:10.1016/j.neurobiolaging.2015.10.029

Cited by 18 publications

(13 citation statements)

References 45 publications

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“…A functional study showed that the p.R298H variant produced a moderate effect on PGRN secretion. [11] Our data support the pathogenic role of GRN p.R298H variant in FTD, since it was first found in two Italian sisters with FTD and family history of behavioral disturbances and dementia.…”

Section: Discussionsupporting

confidence: 87%

“…The mutation was detected in only one patient with pathologically confirmed FLTD with ubiquitin-positive inclusions and unknown family history. [10] The same variant was also reported by Karch et al [11] in one FTLD patient presenting at 71 years with a typical corticobasal syndrome and a family history of dementia. A functional study showed that the p.R298H variant produced a moderate effect on PGRN secretion.…”

Section: Discussionsupporting

confidence: 64%

“…In 2016, the same mutation was reported in one FTLD patient with a substantial family history of dementia. [11] The p.R298H is highly conserved across species. Functional prediction analysis by PolyPhen2 (http:// genet ics.…”

Section: Discussionmentioning

confidence: 99%

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A novel phenotype in an Italian family with a rare progranulin mutation

et al. 2022

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Introduction Progranulin (PGRN) is a secreted glycoprotein encoded in humans by the GRN gene, located on chromosome 17q21. Several nonsense and missense pathogenetic GRN mutations have been described. Objective We herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia. Methods Patients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening. Results The younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H). Conclusions Our report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 64%

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A novel phenotype in an Italian family with a rare progranulin mutation

et al. 2022

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“…Most pathogenic alterations in GRN gene are either frameshift or nonsense mutations causing premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay [ 18 ]. However, point mutations disrupting the structure of the protein are also strongly suspected to be pathogenic [ 19 ]. Loss-of-function mutations in the GRN gene cause haploid insufficiency of progranulin, whose plasma levels decrease as a consequence [ 20 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

Unravelling Genetic Factors Underlying Corticobasal Syndrome: A Systematic Review

Arienti

Lazzeri

Vizziello

et al. 2021

Cells

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Corticobasal syndrome (CBS) is an atypical parkinsonian presentation characterized by heterogeneous clinical features and different underlying neuropathology. Most CBS cases are sporadic; nevertheless, reports of families and isolated individuals with genetically determined CBS have been reported. In this systematic review, we analyze the demographical, clinical, radiological, and anatomopathological features of genetically confirmed cases of CBS. A systematic search was performed using the PubMed, EMBASE, and Cochrane Library databases, included all publications in English from 1 January 1999 through 1 August 2020. We found forty publications with fifty-eight eligible cases. A second search for publications dealing with genetic risk factors for CBS led to the review of eight additional articles. GRN was the most common gene involved in CBS, representing 28 out of 58 cases, followed by MAPT, C9ORF72, and PRNP. A set of symptoms was shown to be significantly more common in GRN-CBS patients, including visuospatial impairment, behavioral changes, aphasia, and language alterations. In addition, specific demographical, clinical, biochemical, and radiological features may suggest mutations in other genes. We suggest a diagnostic algorithm to help in identifying potential genetic cases of CBS in order to improve the diagnostic accuracy and to better understand the still poorly defined underlying pathogenetic process.

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“…Variants in GRN were detected in three subjects (3%). Two carried the same mutation (c.G314A, p.C105Y), previously shown to affect both the secretion of PGRN in cultured cells and the elastase cleavage of PGRN into GRN 24 . One patient (RSA_bvFTD_50) referred as apparently sporadic, carried two different variants in GRN .…”

Section: Resultsmentioning

confidence: 99%

Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

Sassi

Capozzo

Hammer

et al. 2021

Sci Rep

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Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.

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Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features

Cited by 18 publications

References 45 publications

A novel phenotype in an Italian family with a rare progranulin mutation

A novel phenotype in an Italian family with a rare progranulin mutation

Unravelling Genetic Factors Underlying Corticobasal Syndrome: A Systematic Review

Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

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