Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage

Smith, Katherine R.; Damiano, John A.; Franceschetti, Silvana; Carpenter, Stirling; Canafoglia, Laura; Morbin, Michela; Rossi, Giacomina; Pareyson, Davide; Mole, Sara; Staropoli, John F.; Sims, Katherine B.; Lewis, Jada; Lin, Wen Lang; Dickson, Dennis W.; Dahl, Hans Henrik M.; Bahlo, Melanie; Berkovic, Samuel F.

doi:10.1016/j.ajhg.2012.04.021

Cited by 425 publications

(394 citation statements)

References 33 publications

Supporting

Mentioning

387

Contrasting

Order By: Relevance

“…We particularly considered variants close to splice sites and frameshift indels. Next, we prioritized the resulting variant list according to evolutionary conservation and filtered out regions with PhyloP [18] value<0.95; then retained variants predicted as "deleterious/damaging" by PolyPheN [19] and SIFT [20]. At last, we considered biological and clinical relevance of cerebellar ataxia for the identified candidates.…”

Section: Exome Sequencing Data Analysismentioning

confidence: 99%

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

et al. 2014

View full text Add to dashboard Cite

Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G>A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ERlysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.

show abstract

Section: Exome Sequencing Data Analysismentioning

confidence: 99%

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Two homozygous GRN-deficient patients have been recently reported (30). These patients presented with adult onset neuronal ceroid lipofuscinosis (NCL), suffering from progressive loss of vision, retinal dystrophy, cerebellar ataxia, and seizures (Table 1).…”

Section: Homozygous Progranulin Mutation Causes Neuronal Ceroid Lipofmentioning

confidence: 99%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

207

196

View full text Add to dashboard Cite

GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin: The BasicsProgranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1-5). In the brain, intracellular expression is highest in neurons and activated microglia (6 -8). At the subcellular level, progranulin colocalizes with the endoplasmic reticulum and Golgi markers in the secretory pathway and the lysosomal marker Lamp1 (9, 10). Progranulin is a secreted glycoprotein and is readily detected in blood and cerebrospinal fluid (11)(12)(13).Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These "granulins" were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. Progranulin Haploinsufficiency Causes Frontotemporal Lobar Degeneration with Ubiquitinated TDP-43-positive InclusionsIn 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3 with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15,16). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5-15% of all dementias (17,18). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19).Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocam...

show abstract

“…Patients with a homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis (NCL), a group of neurodegenerative lysosomal storage disorders [12]. Additionally, Götzl et al (2014) recently revealed that FTLD patients due to PGRN deficiency have NCLlike pathology [13].…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

View full text Add to dashboard Cite

Introduction: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10-and 90-week-old wild-type and PGRN-deficient mice. Results: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.

show abstract

Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage

Cited by 425 publications

References 33 publications

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Contact Info

Product

Resources

About