Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Abstract

Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase

“…Human cervical carcinoma (HeLa) cells, human embryonic kidney (HEK 293T) cells, and mouse embryonic fibroblasts (MEFs) from autophagy-related gene-5 (ATG-5) knock-out and wild type (wt) mice (Mizushima et al, 2001) were cultured in DMEM with Glutamax I (Invitrogen). Lymphoblasts, immortalized by Ebstein Barr virus transformation of lymphocytes collected from whole blood on lithium heparin according to standard procedures Gijselinck et al, 2008), were cultured in RPMI 1640 medium (Invitrogen) with glutamine (Invitrogen). Mouse neuroblastoma cells (N2a) were cultured in modified Eagle's medium (MEM) with glutamine.…”

“…Deposited proteins observed in FTLD-U brains include the TAR-DNA binding protein 43 (Neumann et al, 2006)] and the fused in sarcoma protein [FUS (FTLD-FUS)] (Neumann et al, 2009). Genetic linkage studies and/or mutation screenings identified loss-of-function mutations in the progranulin gene (GRN ) in patients with familial FTLD-TDP (Baker et al, 2006;Cruts et al, 2006;Cruts and Van Broeckhoven, 2008;Gijselinck et al, 2008). Of the mutations reported to date (http:// www.molgen.vib-ua.be/FTDMutations/), most are loss-offunction mutations leading to GRN haploinsufficiency , which results in a severe reduction of GRN levels in tissues and biological fluids of patients (Ghidoni et al, 2008;Finch et al, 2009;Sleegers et al, 2009).…”

The granulin gene family: from cancer to dementia

“…(6,7) Presently the Alzheimer Disease and Frontotemporal Dementia Mutation Database (http:// www.molgen.ua.ac.be/FTDMutations/) records 66 distinct GRN mutations. (58) Most, if not all the GRN-dependent FTDs result from a decrease in the amount of PGRN expressed or secreted, rather than an acquired toxic effect of mutant protein. Many of these mutations lead to nonsense-mediated mRNA decay, a process that eliminates the mutant transcripts and therefore lowers the expression level of PGRN mRNA by 50%.…”

GRN mutation in a patient with a behavioral variant of frontotemporal lobar degeneration (bvFTD)

“…This may explain the parkinsonism that is frequently associated with the disease even in its early stages. There are some case reports describing the loss of pigmented neurons from the substantia nigra [9,15,19]. Here we describe a case of a patient with a rare splicing mutation in the GRN gene and unilateral caudate nucleus atrophy.…”