GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil

Abstract

Background Mutations in GRN (progranulin) and MAPT (microtubule-associated protein tau) are among the most frequent causes of monogenic Frontotemporal Dementia (FTD), but data on the frequency of those mutations in regions such as Latin America is still lacking. Objective We aimed to investigate the frequencies of GRN and MAPT mutations in FTD cohorts from two Brazilian dementia research centers, from University of Sao Paulo (USP) and Federal University of Minas Gerais (UFMG) medical schools. Methods We included 76 probands diagnosed with behavioral variant FTD (n=55), semantic variant Primary Progressive Aphasia (PPA) (n=11), or nonfluent variant PPA (n=10). Twenty-five percent of the cohort had at least one relative affected with FTD. Results Mutations in GRN were identified in seven probands, and in MAPT, in two probands. We identified three novel GRN mutations (p.Q130X, p.317Afs*12, and p.K259Afs*23), in patients diagnosed with nfvPPA or bvFTD. Plasma progranulin levels were measured and a cutoff value of 70ng/ml was found with 100% sensitivity and specificity to detect null GRN mutations. Conclusions The frequency of GRN mutations was 9.6% and of MAPT mutations, was 7.1%. Among familial cases of FTD, the frequency of GRN mutations was 31.5%, and of MAPT mutations was 10.5%.

Genetics of dementia: insights from Latin America

“…His mother also had bvFTD and motor symptoms. 24 Finally, a person with K259Afs GRN mutation and some relatives developed anomia, logorrhea, apathy, disinhibition, diet changes, and asymmetric brain atrophy, especially of the temporal lobes. 24 Regarding MAPT, an Asn279Lys (N279K) mutation was found in a 45 y.o.…”

“…The other proband had a g.120998 cytosine to thymine change, an intronic variant that affects the alternative splicing of exon 10 (IVS10+16 C>T), which does not lead to a protein change but could explain the bvFTD phenotype of this subject. 24 TARDBP is a gene in chromosome 1 that encodes a protein called TDP-43, an important riboprotein with functions such as mRNA stabilization, transcription regulation, and alternative splicing. 6,25 Mutations in this gene have been associated with FTD, FTD-ALS, and ALS.…”

A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia

“…FTD has an important genetic component, since a substantial percentage of the cases (30 to 50%) have at least one first-degree relative with FTD and about 10 to 15% have a family history of FTD with autosomal dominant pattern of inheritance (Goldman et al, 2005;Rohrer et al, 2009;Takada, 2017;Takada et al, 2016). The most common genetic forms of FTD are due to mutations in C9orf72, MAPT and GRN genes (Galimberti et al, 2015;Sieben et al, 2012), explaining 17% of the familial FTD (Sieben et al, 2012).…”

A review on shared clinical and biological aspects of bipolar disorder and frontotemporal dementia

“…Plasma and CSF levels of proteins encoded by the genes associated with genetic forms of FTD have been studied as biomarkers. Progranulin, a protein encoded by the GRN gene, was found to be 3.93 times lower in affected and unaffected GRN carriers (Ghidoni et al, 2008;Takada et al, 2016). Furthermore, it was possible to establish a cut-off among mutation carriers with and without FTD clinical symptoms.…”

“…FTD has an important genetic component, since a substantial percentage of cases (30 to 50%) have at least one first-degree relative with FTD and about 10 to 15% have a family history of FTD with autosomal dominant pattern of inheritance (Goldman et al, 2005;Rohrer et al, 2009;Takada, 2017;Takada et al, 2016). explaining 17% of the variance in FTD subjects (Sieben et al, 2012).…”