Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation

Almeida, Maria Rosário; Macário, Maria Carmo; Ramos, Lina; Baldeiras, Inês; Ribeiro, Maria Helena; Santana, Isabel

doi:10.1016/j.neurobiolaging.2016.02.019

Cited by 108 publications

(98 citation statements)

References 20 publications

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“…We also found that lipofuscinosis and membrane-bound storage material deposition—pathologic hallmarks of NCL—occurred in heterozygous GRN mutation carriers, consistent with what has been seen in homozygous GRN mutation carriers. A recent finding that an NCL case caused by a homozygous GRN mutation segregated in a family with neuropathologically confirmed FTLD further supports the notion that PGRN-deficient NCL and FTLD are pathophysiologically related (19). …”

Section: Discussionmentioning

confidence: 59%

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

et al. 2017

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Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

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Section: Discussionmentioning

confidence: 59%

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

et al. 2017

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“…Interestingly, even though FTLD is a neurodegenerative disorder that affects older adults, previous studies have identified shared genetic risk factors between NCL and FTLD. Heterozygous GRN pathogenic variants cause about 10% of all FTD cases, while homozygous recessive pathogenic variants in GRN have been linked to recessive adult-onset NCL in two separate families [3, 6, 7, 11, 69, 79]. More recently, Ward and colleagues provided further evidence for phenotypic overlap between FTLD and NCL due to pathogenic GRN variants by identifying NCL-like biological hallmarks in haploinsufficient GRN patients [75].…”

Section: Discussionmentioning

confidence: 99%

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

et al. 2018

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Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3,541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 associates with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus (MFG) of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed increases in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

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“…Individuals who carry two mutant GRN alleles, and thus completely lack progranulin and its cleavage products (functional null), develop a lysosomal storage disease that is now known as NCL (or ceroid neuronal lipofuscinosis-11 (CLN11)) 10,11,40 . These patients have undetectable levels of progranulin in the plasma and develop neurological deficits, such as vision loss, myoclonic seizures and cerebellar ataxia between 20 and 30 years of age.…”

Section: Progranulin Dosage and Diseasementioning

confidence: 99%

“…In the ensuing decade, several potential functions have been proposed for progranulin in the CNS, ranging from trophic factor support for neurons to suppression of microglial activation 9 , but the exact mechanism by which GRN haploinsufficiency results in neurodegeneration remains poorly understood. The discovery that patients with homozygous GRN mutations developed neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease, has drawn further attention to progranulin position in the lysosome and its potential role in neuronal proteostasis 10,11 .…”

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confidence: 99%

Progranulin, lysosomal regulation and neurodegenerative disease

et al. 2017

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Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation

Cited by 108 publications

References 20 publications

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

Progranulin, lysosomal regulation and neurodegenerative disease

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