Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Abstract

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…FTLD patients with an underlying TDP43 pathology (FTLD‐TDP, n  = 30) were selected based on autopsy ( n  = 8) and C9orf72 /GRN mutations ( n  = 15) 13, 14. Diagnostic groups were enriched with CSF from patients with FTLD‐Plus syndromes that reflect high correlation with a specific neuropathology.…”

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

“…In the CNS, progranulin expression increases with age in both neurons and microglia, and plays a role in neurite outgrowth, synapse modification, and the prevention of neuronal apoptosis 1, 2, 3, 4. This neuroprotective function is highlighted by the relationship between progranulin and neurodegenerative disease; heterozygous loss‐of‐function mutations in the gene encoding progranulin ( GRN ) cause frontotemporal dementia (FTD),5, 6 and a common rs5848 allele in the 3′UTR of GRN has been associated with both decreased serum and brain progranulin expression levels and increased risk of developing Alzheimer's disease (AD) 7, 8, 9. Additionally, misregulation of progranulin expression has been implicated in parkinsonism, neuronal ceroid lipofuscinosis, and other neuropsychiatric disorders 10, 11…”

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

“…It has a role in anti-inflammatory processes, but it can be proteolitically cleaved in granulins, which, conversely, act as proinflammatory mediators. 1 In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. 2 Other evidence can be found about increased levels of GRN mRNA in several inflammatory neurodegenerative disorders associated with microglial activation, such as amyotrophic lateral sclerosis 3 and virally induced central nervous system inflammation.…”