Progranulin Gene (GRN), Full Gene Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Frontotemporal lobar degeneration (FTLD) describes a group of neurodegenerative diseases that are frequent causes of dementia, accounting for 5% to 10% of all dementia patients and 10% to 20% of patients with onset of dementia before age 65. Frontotemporal dementia (FTD) is the most common clinical manifestation of FTLD. The clinical presentation of FTD is variable, but typically includes changes in personality and social conduct, often associated with impulse disinhibition, followed by more general cognitive decline, eventually leading to dementia. The age of onset is extremely variable ranging from 35 to 87 years. Duration of the disease ranges from 3 to 12 years.
Based on the immunohistochemical staining, there are 2 main subtypes of FTLD: tau-positive FTLD and tau-negative FTLD with ubiquitin-positive inclusions (FTLD-U). Mutations in the MAPT gene have been identified in patients with tau-positive FTLD; mutations in the progranulin gene (GRN) have been identified in patients with FTLD-U. Both MAPT and GRN are located on chromosome 17q21, with GRN located only 1.7 Mb centromeric of MAPT. GRN consists of 12 coding and 1 noncoding exons.
GRN encodes progranulin, a multifunctional protein that plays a role in multiple processes including development, wound repair, and inflammation. The function of GRN in the brain is not well understood, but progranulin is widely expressed in neurons and glial cells. More than 40 different pathogenic GRN mutations have been reported. All pathogenic mutations identified to date create functional null alleles that result in decreased progranulin production, suggesting that reduced levels of progranulin may lead to neurodegeneration.
Aiding the diagnosis of frontotemporal dementia
Distinguishing frontotemporal dementia from other dementias, including Alzheimer dementia
Identifying individuals who are at increased risk of frontotemporal dementia
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Some individuals who are carriers or have a diagnosis of frontotemporal dementia may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). Mutations in other genes have also been implicated in frontotemporal dementia. Abnormalities in other genes are not detected by this assay. The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of frontotemporal dementia. For carrier testing, it is important to first document the presence of a GRN gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Rademakers R, Hutton M: The genetics of frontotemporal lobar degeneration. Curr Neurol Neurosci Rep. 2007 Sep;7(5):434-42
2. Gass J, Cannon A, Mackenzie IR, et al: Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Molec Genet 2006 Oct 15, 15(20):2988-3001
3. Cruts M, Gijselinck I, van der Zee J, et al: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006 Aug 24, 442(7105):920-924
4. Eriksen JL, Mackenzie IR: Progranulin: normal function and role in neurodegeneration. J Neurochem 2008;104:287-297