Genetics of FTD

Up to 50% of FTD patients have positive family history of dementia, mainly with autosomal dominant inheritance. FTD is a genetically complex disorder with several genes associated with disease etiology (http://www.molgen.ua.ac.be/ADMutations), including the MAPT and GRN genes responsible for the disease in FTD families linked to chromosome 17q21.The most common mutation reported to date is an expanded hexanucleotide repeat in a non-coding region of C9orf72, which is the cause of chromosome 9p21-linked FTD and Amyotrophic lateral sclerosis (ALS) with TDP-43/p62 associated brain pathology.

Genes most often associated with FTD

[simple_tooltip content=’Onset—Patients bearing the c.1145insA were more distracted, with slight impairment of planning, and had a tendency for greater behavioural disinhibition when compared with GRN_negative cases or with carriers of the A266P or C126W mutations. Reduction of verbal output and apathy were common to all but one group (C126W) in different percentages. Patients with the c.1145insA patients showed primitive reflexes and extrapyramidal signs early (50% and 42% respectively); neurological signs were absent in the other GRN_positive patients. GRN_negative patients had 33% rigidity and stereotypies. Manifest stage—The c.1145insA carriers were more distracted and disinhibited with greater alteration of social behaviour; language disorder evolved to complete mutism; A266P carriers showed apathy in 100% of cases, emotional unconcern, greater hyperorality, extrapyramidal signs, pyramidal signs in 67% of cases; C126W patients presented with paranoid delusions, disinhibition, agitation and extrapyramidal signs’]GRN[/simple_tooltip]

More on GRN

Progranulin burst on the scene of neurodegenerative disease as a major genetic cause of frontotemporal dementia (FTD) in 2006, only months before TDP-43 was identified as the main protein constituent of the histopathological lesions in the same patients. Up to that point, the only known FTD gene had been MAPT, located near the progranulin gene, GRN, on chromosome 17q21, and the twin discoveries broke a double logjam in the field. The roughly 70 GRN mutations known to date explain all 17q21-linked autosomal-dominant FTD families not accounted for by tau mutations, and because all FTD patients with a GRN mutation have TDP-43 pathology, TDP-43 explains these family’s tau-negative protein inclusions. GRN mutations explain up to 20 percent of familial and 5 percent of sporadic FTD. Histopathological commonalities notwithstanding, GRN mutations lead to a variety of clinical presentations, causing mostly behavioral FTD and progressive nonfluent aphasia, but also rare presentations of Alzheimer’s disease or parkinsonism. All pathologic GRN mutations reduce progranulin levels or result in loss of function. Indeed, blood progranulin levels indicate the presence of a pathogenic progranulin mutation and are rapidly becoming a diagnostic biomarker. Progranulin is a secreted growth factor known for its role in biological processes such as inflammation, wound healing, and cancer, and for its neurotrophic properties. It is proteolytically processed into peptides called granulins, which are poorly understood. Progranulin’s role in FTD is being investigated in parallel with potential therapeutic approaches aimed at increasing its levels in the CNS.Several factors are known to influence progranulin expression. They include intrinsic factors, for example the gene TMEM106B and various microRNAs, as well as pharmacological agents, such as the histone deacetylase inhibitor SAHA and certain alkalizing drugs. Agents targeting the endocytic progranulin receptor sortilin-1 appear to increase plasma progranulin levels by slowing its internalization. Homozygous GRN mutations cause the rare lysosomal storage disease ceroid lipofuscinosis, and progranulin localizes to intraneuronal membrane compartments, including lysosomes. Both homozygous and heterozygous GRN knockout mice exist; the former show both behavioral and inflammatory phenotypes, the latter develop only the former. (From Alzgene).

MAPT
C9orf72
TMEM106B

Known GRN mutations have different pathogenic potential depending on the type of mutation (i.e. deletion, nonsense, frameshift, splice-site and some missense substitutions), causing FTD with different degrees of severity. Recently, it was demonstrated that plasma progranulin protein levels could predict the presence of GRN mutations in FTD patients and that it may be a valuable tool in predicting the pathogenic significance of GRN mutations. However, different clinical characteristics are observed in carriers of the same GRN mutation, even within the same family. Some of this clinical variability could be explained by specific variants of a modifying gene. Common variations in the GRN gene (rs9897526, rs5848) and the Transmembrane protein 106B gene (TMEM106B) (rs1990622, rs1020004) were reported to influence age of onset.

Reference

Neurobiol Aging. 2012 Dec; 33(12): 2948.e1–2948.e10.

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