A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review

Hosaka, Takashi; Ishii, Kazuhiro; Miura, Takeshi; Mezaki, Naomi; Kasuga, Kensaku; Ikeuchi, Takeshi; Tamaoka, Akira

doi:10.1186/s12883-017-0959-2

Cited by 12 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GRN mutations are rare in Asian cohorts and absent in Korea and Hong Kong [16][17][18][19][20][21]. Four GRN mutations were reportedly associated with positive family history of FTLD: the first was in 2 Chinese sisters with CBS [22], then a Japanese female individual with primary progressive aphasia and mother with dementia [17], a patient with bvFTD from South India [18], and a Japanese with primary progressive aphasia whose brother had CBS [23]. They would be category 2-3 by Goldman's criteria [6].…”

Section: Discussionmentioning

confidence: 99%

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Dominguez

et al. 2020

Dement Geriatr Cogn Disord

View full text Add to dashboard Cite

Background: Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. Case Presentation: The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. Conclusion: This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.

show abstract

Section: Discussionmentioning

confidence: 99%

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Dominguez

et al. 2020

Dement Geriatr Cogn Disord

View full text Add to dashboard Cite

show abstract

“…Similarly, whilst cases have been reported, MAPT 52,53 and GRN mutations remain less prevalent amongst Asian compared to Western cohorts 50,55,56 . A South Korean study found 2 novel missense variants of unknown significance in both MAPT and GRN in 2% of patients but did not identify any pathogenic variants 15 .…”

Section: Discussionmentioning

confidence: 92%

“…47 Similarly, whilst cases have been reported, MAPT 52,53 and GRN mutations remain less prevalent amongst Asian compared to Western cohorts. 50,55,56 A South Korean study found 2 novel missense variants of unknown significance in both MAPT and GRN in 2% of patients but did not identify any pathogenic variants. 15 In our cohort, four pathogenic/likely pathogenic mutations in GRN were observed in 3 nfvPPA/indeterminant PPA and 1 bvFTD; one VUS in nfvPPA/indeterminant PPA.…”

Section: Discussionmentioning

confidence: 99%

C9orf72 expansions are the most common cause of genetic frontotemporal dementia in a Southeast Asian cohort

Tan

Yong

Foo

et al. 2023

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Objective Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative disorders, including behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non‐fluent variant PPA (nfvPPA). While a strong genetic component is implicated in FTD, genetic FTD in Asia is less frequently reported. We aimed to investigate the frequency of Southeast Asian FTD patients harbouring known genetic FTD variants. Methods A total of 60 FTD‐spectrum patients (25 familial and 35 sporadic) from Singapore and the Philippines were included. All underwent next‐generation sequencing and repeat‐primed PCR for C9orf72 expansion testing. Neurofilament light chain (NfL) levels were measured in a subset of patients. Results Overall, 26.6% (16/60 cases) carried pathogenic or likely pathogenic variants in a FTD‐related gene, including: MAPT Gln351Arg (n = 1); GRN Cys92Ter (n = 1), Ser301Ter (n = 2), c.462 + 1G > C (n = 1); C9orf72 expansion (35–70 repeats; n = 8); TREM2 Arg47Cys (n = 1); and OPTN frameshift insertion (n = 2). Genetic mutations accounted for 48% (12/25) of patients with familial FTD, and 11.4% (4/35) of patients with sporadic FTD. C9orf72 repeat expansions were the most common genetic mutation (13.3%, 8/60), followed by GRN (6.7%, 4/60) variants. Within mutation carriers, plasma NfL was highest in a C9orf72 expansion carrier, and CSF NfL was highest in a GRN splice variant carrier. Interpretation In our cohort, genetic mutations are present in one‐quarter of FTD‐spectrum cases, and up to half of those with family history. Our findings highlight the importance of wider implementation of genetic testing in FTD patients from Southeast Asia.

show abstract

“…The GRN A9D missense mutation disrupts the signal sequence of the progranulin peptide, thus preventing both its lysosomal localization and secretion into the extracellular space [44,[46][47][48]. Other missense and splice site mutations cause frameshifts or large genomic deletions that result in aberrant protein products ultimately destined for ER-associated degradation [49,50]. Two pathogenic cysteine mutations, C521Y and C139R, do not cause progranulin haploinsufficiency but abolish progranulin's neurotrophic effects in vitro and may impact progranulin's proteolytic cleavage, which is necessary for production of functional granulins [51].…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

2023

View full text Add to dashboard Cite

Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising progranulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant allele, as well as approaches to directly increase progranulin levels by delivery across the blood–brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be the next frontier in the treatment of neurodegenerative disease.

show abstract

A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review

Cited by 12 publications

References 23 publications

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation

C9orf72 expansions are the most common cause of genetic frontotemporal dementia in a Southeast Asian cohort

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

Contact Info

Product

Resources

About