Abstract
Granulin (GRN) mutations were first found in frontotemporal dementia (FTD) patients with ubiquitin-positive, tau-negative inclusions in 2006. These inclusions were also found to contain a TAR-DNA binding protein of 43 kDa (TDP-43). PGRN protein itself is not a component of ubiquitin-positive inclusion bodies. Since then, more than 190 GRN mutations have been reported, including substitutions, insertions, and deletions. The common pathological mechanism observed with these mutations was proposed to arise from haploinsufficiency; the amount of functional PGRN was reduced to half of the normal level. In fact, GRN mutation carriers showed significantly reduced expression levels of PGRN in plasma and serum. Immunohistochemical analyses of phosphorylated TDP-43 revealed that cases of FTLD-TDP with a GRN mutation invariably display type A pathology, which is characterized by numerous short dystrophic neurites (DNs) and crescentic or oval shaped neuronal cytoplasmic inclusions (NCIs). GRN mutations were initially found in FTD patients with tau-negative, TDP-43-positive inclusions, however, recent findings suggested that different clinical phenotypes may be seen in the same GRN mutation carriers and additional tau or α-synuclein accumulation may be observed.
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References
Almeida MR et al (2014) Progranulin peripheral levels as a screening tool for the identification of subjects with progranulin mutations in a Portuguese cohort. Neurodegener Dis 13:214–223. https://doi.org/10.1159/000352022
Arai T et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611. https://doi.org/10.1016/j.bbrc.2006.10.093
Arosio B et al (2013) GRN Thr272fs clinical heterogeneity: a case with atypical late onset presenting with a dementia with Lewy bodies phenotype. J Alzheimers Dis 35:669–674. https://doi.org/10.3233/JAD-130053
Aswathy PM, Jairani PS, Raghavan SK, Verghese J, Gopala S, Srinivas P, Mathuranath PS (2016) Progranulin mutation analysis: identification of one novel mutation in exon 12 associated with frontotemporal dementia. Neurobiol Aging 39:218 e211–218 e213. https://doi.org/10.1016/j.neurobiolaging.2015.11.026
Baker M et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919. https://doi.org/10.1038/nature05016
Barandiaran M et al (2012) Neuropsychological features of asymptomatic c.709-1G>A progranulin mutation carriers. J Int Neuropsychol Soc 18:1086–1090. https://doi.org/10.1017/S1355617712000823
Beck J et al (2008) A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain J Neurol 131:706–720. https://doi.org/10.1093/brain/awm320
Behrens MI et al (2007) Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation. Alzheimer Dis Assoc Disord 21:1–7. https://doi.org/10.1097/WAD.0b013e31803083f2
Benussi L, Binetti G, Sina E, Gigola L, Bettecken T, Meitinger T, Ghidoni R (2008) A novel deletion in progranulin gene is associated with FTDP-17 and CBS. Neurobiol Aging 29:427–435. https://doi.org/10.1016/j.neurobiolaging.2006.10.028
Bernardi L et al (2009) Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging 30:1825–1833. https://doi.org/10.1016/j.neurobiolaging.2008.01.005
Bit-Ivan EN et al (2014) A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases. J Neuropathol Exp Neurol 73:467–473. https://doi.org/10.1097/NEN.0000000000000070
Boeve BF et al (2006) Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study. Brain J Neurol 129:3103–3114. https://doi.org/10.1093/brain/awl268
Borroni B et al (2008) Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series. Neurogenetics 9:197–205. https://doi.org/10.1007/s10048-008-0127-3
Bronner IF et al (2007) Progranulin mutations in Dutch familial frontotemporal lobar degeneration. Eur J Hum Genet 15:369–374. https://doi.org/10.1038/sj.ejhg.5201772
Brouwers N et al (2007) Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol 64:1436–1446. https://doi.org/10.1001/archneur.64.10.1436
Brouwers N et al (2008) Genetic variability in progranulin contributes to risk for clinically diagnosed. Alzheimer disease. Neurology 71:656–664. https://doi.org/10.1212/01.wnl.0000319688.89790.7a
Bruni AC et al (2007) Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation. Neurology 69:140–147. https://doi.org/10.1212/01.wnl.0000265220.64396.b4
Cairns NJ et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240. https://doi.org/10.2353/ajpath.2007.070182
Calvi A et al (2015) The novel GRN g.1159_1160delTG mutation is associated with behavioral variant frontotemporal dementia. J Alzheimers Dis 44:277–282
Carecchio M et al (2009) Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer’s disease. J Neurol Sci 287:291–293. https://doi.org/10.1016/j.jns.2009.07.011
Carecchio M et al (2014) Evidence of pre-synaptic dopaminergic deficit in a patient with a novel progranulin mutation presenting with atypical parkinsonism. J Alzheimers Dis 38:747–752. https://doi.org/10.3233/JAD-131151
Cerami C, Marcone A, Galimberti D, Villa C, Fenoglio C, Scarpini E, Cappa SF (2013) Novel missense progranulin gene mutation associated with the semantic variant of primary progressive aphasia. J Alzheimers Dis 36:415–420. https://doi.org/10.3233/JAD-130317
Chang KH et al (2018) Genetic and functional characters of GRN p.T487I mutation in Taiwanese patients with atypical parkinsonian disorders. Parkinsonism Relat Disord 51:61–66. https://doi.org/10.1016/j.parkreldis.2018.02.045
Chiang HH et al (2008) Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family. Alzheimers Dement 4:414–420. https://doi.org/10.1016/j.jalz.2008.09.001
Cioffi SM et al (2016) Non fluent variant of primary progressive aphasia due to the novel GRN g.9543delA(IVS3-2delA) mutation. J Alzheimers Dis 54:717–721. https://doi.org/10.3233/JAD-160185
Clot F et al (2014) Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration. Neurogenetics 15:95–100. https://doi.org/10.1007/s10048-014-0389-x
Coppola G et al (2008) Gene expression study on peripheral blood identifies progranulin mutations. Ann Neurol 64:92–96. https://doi.org/10.1002/ana.21397
Coppola C et al (2012) A progranulin mutation associated with cortico-basal syndrome in an Italian family expressing different phenotypes of fronto-temporal lobar degeneration. Neurol Sci 33:93–97. https://doi.org/10.1007/s10072-011-0655-8
Cortini F et al (2008) Novel exon 1 progranulin gene variant in Alzheimer’s disease. Eur J Neurol 15:1111–1117. https://doi.org/10.1111/j.1468-1331.2008.02266.x
Cruchaga C et al (2009) Cortical atrophy and language network reorganization associated with a novel progranulin mutation. Cereb Cortex 19:1751–1760. https://doi.org/10.1093/cercor/bhn202
Cruts M et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924. https://doi.org/10.1038/nature05017
Cruts M, Theuns J, Van Broeckhoven C (2012) Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 33:1340–1344. https://doi.org/10.1002/humu.22117
Cupidi C, Manna I, Navarra V, Vena L, Realmuto S, Cerami C, Quattrone A, Gambardella A, Piccoli F, Piccoli T (2009) Identification of three novel progranulin mutations in a series of patients affected by sporadic and familial frontotemporal lobar degeneration. Alzheimers Demen 5:P406
Davion S et al (2007) Clinicopathologic correlation in PGRN mutations. Neurology 69:1113–1121. https://doi.org/10.1212/01.wnl.0000267701.58488.69
Del Bo R et al (2011) No major progranulin genetic variability contribution to disease etiopathogenesis in an ALS Italian cohort. Neurobiol Aging 32:1157–1158. https://doi.org/10.1016/j.neurobiolaging.2009.06.006
Dopper EG et al (2011) Symmetrical corticobasal syndrome caused by a novel C.314dup progranulin mutation. J Mol Neurosci 45:354–358. https://doi.org/10.1007/s12031-011-9626-z
Finch N et al (2009) Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain J Neurol 132:583–591. https://doi.org/10.1093/brain/awn352
Frangipane FCR, Mirabelli M, Puccia G, Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Maletta R, Smirne N, Elder J, Kawarai T, Sato C, Pradella S, Wakutani Y, Dertesz A, St George Hyslop P, Hardy J, Rogaeva E, Momeni P, Bruni AC (2008) A novel progranulin mutation in a large frontotemporal dementia Calabrian kindred. Alzheimers Dement 4:T604
Galimberti DFC, Cortini F, Venturelli E, Guidi I, Scalabrini D, Villa C, Marcone A, Mandelli A, Perini L, Pomati S, Clerici F, Cappa S, Mariani C, Bresolin N, Scarpini E (2008) Progranulin gene mutation scanning in Alzheimer’s disease and frontotemporal lobar degeneration: functional and phenotypic correlations. Alzheimers Dement 4:T585
Gass J et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001. https://doi.org/10.1093/hmg/ddl241
Gazzina S et al (2017) Frontotemporal dementia due to the novel GRN Arg161GlyfsX36 mutation. J Alzheimers Dis 57:1185–1189. https://doi.org/10.3233/JAD-170066
Ghetti B et al (2008) In vivo and postmortem clinicoanatomical correlations in frontotemporal dementia and parkinsonism linked to chromosome 17. Neurodegener Dis 5:215–217. https://doi.org/10.1159/000113706
Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G (2008) Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 71:1235–1239. https://doi.org/10.1212/01.wnl.0000325058.10218.fc
Gibbons L et al (2015) Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration. Neurobiol Aging 36:1603 e1601–1604. https://doi.org/10.1016/j.neurobiolaging.2014.10.023
Gijselinck I et al (2008) Progranulin locus deletion in frontotemporal dementia. Hum Mutat 29:53–58. https://doi.org/10.1002/humu.20651
Gomez-Tortosa E et al (2013) Plasma progranulin levels in cortical dementia phenotypes with asymmetric perisylvian atrophy. Eur J Neurol 20:1319–1324. https://doi.org/10.1111/ene.12211
Guerreiro RJ et al (2008) Novel progranulin mutation: screening for PGRN mutations in a Portuguese series of FTD/CBS cases. Move Disord 23:1269–1273. https://doi.org/10.1002/mds.22078
Guerreiro RJ, Washecka N, Hardy J, Singleton A (2010) A thorough assessment of benign genetic variability in GRN and MAPT. Hum Mutat 31:E1126–E1140. https://doi.org/10.1002/humu.21152
Hosaka T, Ishii K, Miura T, Mezaki N, Kasuga K, Ikeuchi T, Tamaoka A (2017) A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review. BMC Neurol 17:182. https://doi.org/10.1186/s12883-017-0959-2
Hosokawa M et al (2015) Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice. J Neuropathol Exp Neurol 74:158–165. https://doi.org/10.1097/NEN.0000000000000158
Hosokawa M et al (2017) Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation. Sci Rep 7:1513. https://doi.org/10.1038/s41598-017-01587-6
Hosokawa M, Tanaka Y, Arai T, Kondo H, Akiyama H, Hasegawa M (2018) Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer’s disease model mice. Exp Anim 67:63–70. https://doi.org/10.1538/expanim.17-0060
Hsiung GY, Fok A, Feldman HH, Rademakers R, Mackenzie IR (2011) rs5848 polymorphism and serum progranulin level. J Neurol Sci 300:28–32. https://doi.org/10.1016/j.jns.2010.10.009
Huey ED et al (2006) Characteristics of frontotemporal dementia patients with a Progranulin mutation. Ann Neurol 60:374–380. https://doi.org/10.1002/ana.20969
Hutton M et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. https://doi.org/10.1038/31508
Jin SC et al (2012) Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer’s disease. Ibero-American cohort. Alzheimers Res Ther 4:34. https://doi.org/10.1186/alzrt137
Josephs KA et al (2007) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 66:142–151. https://doi.org/10.1097/nen.0b013e31803020cf
Karch CM et al (2016) Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features. Neurobiol Aging 38:215 e211–215 e212. https://doi.org/10.1016/j.neurobiolaging.2015.10.029
Kelley BJ et al (2009) Prominent phenotypic variability associated with mutations in Progranulin. Neurobiol Aging 30:739–751. https://doi.org/10.1016/j.neurobiolaging.2007.08.022
Kelley BJ et al (2010) Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin. Arch Neurol 67:171–177. https://doi.org/10.1001/archneurol.2010.113
Kim G et al (2016) Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions. Neurology 86:627–636. https://doi.org/10.1212/WNL.0000000000002375
Kuuluvainen L et al (2017) A novel loss-of-function GRN mutation p.(Tyr229*): clinical and neuropathological features. J Alzheimers Dis 55:1167–1174. https://doi.org/10.3233/JAD-160647
Le Ber I et al (2007) Progranulin null mutations in both sporadic and familial frontotemporal dementia. Hum Mutat 28:846–855. https://doi.org/10.1002/humu.20520
Le Ber I et al (2008) Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain J Neurol 131:732–746. https://doi.org/10.1093/brain/awn012
Lee JH et al (2014) Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med 2:430–437. https://doi.org/10.1002/mgg3.85
Leverenz JB et al (2007) A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain J Neurol 130:1360–1374. https://doi.org/10.1093/brain/awm069
Lindquist SG, Schwartz M, Batbayli M, Waldemar G, Nielsen JE (2009) Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet 76:205–209. https://doi.org/10.1111/j.1399-0004.2009.01191.x
Lladó A et al (2007) Late-onset frontotemporal dementia associated with a novel PGRN mutation. J Neural Transm 114:1051–1054. https://doi.org/10.1007/s00702-007-0716-6
López de Munain A et al (2008) Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings. Biol Psychiatry 63:946–952. https://doi.org/10.1016/j.biopsych.2007.08.015
Luzzi S et al (2017) Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration. Neurobiol Aging 54:214 e211–214 e216. https://doi.org/10.1016/j.neurobiolaging.2017.02.008
Mackenzie IR, Feldman H (2003) Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases. Acta Neuropathol 105:543–548. https://doi.org/10.1007/s00401-003-0678-1
Mackenzie IR et al (2006a) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549. https://doi.org/10.1007/s00401-006-0138-9
Mackenzie IR et al (2006b) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain J Neurol 129:3081–3090. https://doi.org/10.1093/brain/awl271
Mackenzie IR, Shi J, Shaw CL, Duplessis D, Neary D, Snowden JS, Mann DM (2006c) Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 112:551–559. https://doi.org/10.1007/s00401-006-0123-3
Mackenzie IR et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. https://doi.org/10.1007/s00401-011-0845-8
Mao Q et al (2017) Disease and region specificity of granulin immunopositivities in Alzheimer disease and frontotemporal lobar degeneration. J Neuropathol Exp Neurol 76:957–968. https://doi.org/10.1093/jnen/nlx085
Maquat LE (2004) Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5:89–99
Marcon G et al (2011) Variability of the clinical phenotype in an Italian family with dementia associated with an intronic deletion in the GRN gene. J Alzheimers Dis 26:583–590. https://doi.org/10.3233/JAD-2011-110332
Masellis M et al (2006) Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain J Neurol 129:3115–3123. https://doi.org/10.1093/brain/awl276
McKhann GM et al (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 58:1803–1809
Meeter LH, Patzke H, Loewen G, Dopper EG, Pijnenburg YA, van Minkelen R, van Swieten JC (2016) Progranulin levels in plasma and cerebrospinal fluid in Granulin mutation carriers. Dement Geriatr Cogn Disord Extra 6:330–340. https://doi.org/10.1159/000447738
Mendez MF (2018) Manic behavior and asymmetric right frontotemporal dementia from a novel progranulin mutation. Neuropsychiatr Dis Treat 14:657–662. https://doi.org/10.2147/NDT.S156084
Mesulam M et al (2007) Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol 64:43–47. https://doi.org/10.1001/archneur.64.1.43
Moreno F et al (2009) “Frontotemporoparietal” dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation. Neurology 73:1367–1374. https://doi.org/10.1212/WNL.0b013e3181bd82a7
Mukherjee O et al (2006) HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 60:314–322. https://doi.org/10.1002/ana.20963
Mukherjee O et al (2008) Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat 29:512–521. https://doi.org/10.1002/humu.20681
Neary D et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554
Neumann M et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108
Nuytemans K et al (2008) Progranulin variability has no major role in Parkinson disease genetic etiology. Neurology 71:1147–1151. https://doi.org/10.1212/01.wnl.0000327563.10320.2b
Piaceri I et al (2018) Novel GRN mutations in Alzheimer’s disease and frontotemporal lobar degeneration. J Alzheimers Dis 62:1683–1689. https://doi.org/10.3233/JAD-170989
Pickering-Brown SM et al (2006) Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain J Neurol 129:3124–3126. https://doi.org/10.1093/brain/awl289
Pickering-Brown SM et al (2008) Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 131:721–731. https://doi.org/10.1093/brain/awm331
Pietroboni AM et al (2011) Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred. J Alzheimers Dis 24:253–259. https://doi.org/10.3233/JAD-2011-101704
Pires C et al (2013) Phenotypic variability of familial and sporadic Progranulin p.Gln257Profs*27 mutation. J Alzheimers Dis 37:335–342
Rademakers R et al (2007) Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative. Lancet Neurol 6:857–868. https://doi.org/10.1016/S1474-4422(07)70221-1
Redaelli V et al (2018) Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA-binding protein 43 inclusions) in missense progranulin mutation Cys139Arg. Brain Pathol 28:72–76. https://doi.org/10.1111/bpa.12480
Rohrer JD et al (2008) Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene. Arch Neurol 65:506–513. https://doi.org/10.1001/archneur.65.4.506
Rohrer JD et al (2009) Corticobasal syndrome associated with a novel 1048_1049insG progranulin mutation. J Neurol Neurosurg Psychiatry 80:1297–1298. https://doi.org/10.1136/jnnp.2008.169383
Rohrer JD, Crutch SJ, Warrington EK, Warren JD (2010a) Progranulin-associated primary progressive aphasia: a distinct phenotype? Neuropsychologia 48:288–297. https://doi.org/10.1016/j.neuropsychologia.2009.09.017
Rohrer JD et al (2010b) Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. NeuroImage 53:1070–1076. https://doi.org/10.1016/j.neuroimage.2009.12.088
Rossi G et al (2011) A novel progranulin mutation causing frontotemporal lobar degeneration with heterogeneous phenotypic expression. J Alzheimers Dis 23:7–12. https://doi.org/10.3233/JAD-2010-101461
Rovelet-Lecrux A et al (2008) Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease. Neurobiol Dis 31:41–45. https://doi.org/10.1016/j.nbd.2008.03.004
Sassi C et al (2014) Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer’s disease. Neurobiol Aging 35:2881 e2881–2881 e2886. https://doi.org/10.1016/j.neurobiolaging.2014.06.002
Sassi C et al (2016) A novel splice-acceptor site mutation in GRN (c.709-2 A>T) causes frontotemporal dementia Spectrum in a large family from southern Italy. J Alzheimers Dis 53:475–485. https://doi.org/10.3233/JAD-151170
Schlachetzki JC, Schmidtke K, Beckervordersandforth J, Borozdin W, Wilhelm C, Hull M, Kohlhase J (2009) Frequency of progranulin mutations in a German cohort of 79 frontotemporal dementia patients. J Neurol 256:2043–2051. https://doi.org/10.1007/s00415-009-5248-6
Schymick JC et al (2007) Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes. J Neurol Neurosurg Psychiatry 78:754–756. https://doi.org/10.1136/jnnp.2006.109553
Sieben A et al (2018) Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family. Alzheimers Res Ther 10:7. https://doi.org/10.1186/s13195-017-0334-y
Skoglund L, Englund E, Ingelsson M, Lannfelt L, Passant U, Glaser A (2007) Mutation analysis of the progranulin gene in a Scandinavian frontotemporal dementia population. Neurodegener Dis 4:38
Skoglund L et al (2009) Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation. Neurogenetics 10:27–34. https://doi.org/10.1007/s10048-008-0155-z
Sleegers K et al (2008) Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 71:253–259. https://doi.org/10.1212/01.wnl.0000289191.54852.75
Sleegers K et al (2009) Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol 65:603–609. https://doi.org/10.1002/ana.21621
Snowden JS, Pickering-Brown SM, Mackenzie IR, Richardson AM, Varma A, Neary D, Mann DM (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain J Neurol 129:3091–3102. https://doi.org/10.1093/brain/awl267
Spina S, Murrell JR, Huey ED, Wassermann EM, Pietrini P, Grafman J, Ghetti B (2007) Corticobasal syndrome associated with the A9D Progranulin mutation. J Neuropathol Exp Neurol 66:892–900. https://doi.org/10.1097/nen.0b013e3181567873
Spina SMJ, Vidal R, Ghetti B (2008) Neuropathologic and genetic characterization of frontotemporal lobar degeneration with Ubiquitin- and/or Tdp-43-positive inclusions: a large series. Alzheimers Dement 4:T431
Takahashi H et al (2017) Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathol 133:785–807. https://doi.org/10.1007/s00401-017-1668-z
Tanaka Y et al (2017) Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. Hum Mol Genet 26:969–988. https://doi.org/10.1093/hmg/ddx011
Tremolizzo L et al (2009) Higher than expected progranulin mutation rate in a case series of Italian FTLD patients. Alzheimer Dis Assoc Disord 23:301. https://doi.org/10.1097/WAD.0b013e31819e0cc5
Van Deerlin VM et al (2007) Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol 64:1148–1153. https://doi.org/10.1001/archneur.64.8.1148
van der Zee J et al (2007) Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. Hum Mutat 28:416. https://doi.org/10.1002/humu.9484
Wilkie AO (1994) The molecular basis of genetic dominance. J Med Genet 31:89–98
Wong SH, Lecky BR, Steiger MJ (2009) Parkinsonism and impulse control disorder: presentation of a new progranulin gene mutation. Move Dis 24:618–619. https://doi.org/10.1002/mds.22429
Woulfe J, Kertesz A, Munoz DG (2001) Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol 102:94–102
Yu CE et al (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67:161–170. https://doi.org/10.1001/archneurol.2009.328
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Hosokawa, M., Arai, T. (2019). Progranulin and Frontotemporal Lobar Degeneration. In: Hara, H., Hosokawa, M., Nakamura, S., Shimohata, T., Nishihara, M. (eds) Progranulin and Central Nervous System Disorders. Springer, Singapore. https://doi.org/10.1007/978-981-13-6186-9_3
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