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PubMed2026

Protective TMEM106B-rs3173615 delays age at onset in GRN mutation carriers.

One of the major causative genes involved in Frontotemporal dementia (FTD) is Granulin (GRN), encoding for Progranulin (PGRN). GRN mutation carriers show a substantial heterogeneity with high variability in age at onset and pathological presentation, even within the same family or identical mutations, suggesting the presence of additional genetic factors. Single nucleotide polymorphisms in the Transmembrane protein 106B (TMEM106B) locus were identified as a genetic risk-associated factor for FTD. The top variant identified was the non-coding rs1990622, with the major allele (T) associated with an increased risk to develop FTD, while subjects with the minor allele (C) were less likely to develop disease, suggesting a protective effect. In this study, we investigate in a large Italian cohort of GRN mutation carriers, how the coding variant TMEM106B-rs3173615, in linkage disequilibrium with rs1990622, modulates age at onset, survival, and PGRN levels, including, up to date, the highest sample size of homozygous protective allele carriers. Genetic screening for TMEM106B-rs3173615 was performed on a total of 187 GRN mutation carriers, comprising 131 FTD patients and 56 pre-symptomatic subjects. Individuals with the protective genotype (GG) had a risk of FTD onset reduced by 80%, with a median age at onset of 77 years compared to a median age at onset of 63 years for individuals without the protective genotype. TMEM106B-rs3173615 acts as a genetic modifier of age at onset in the presence of GRN mutations and could be considered in clinical practice to optimize risk stratification for FTD.

Humans↗

PubMed2026

GRN rs5848 variant associates with TDP-43 pathology and cancer in opposite directions.

Epidemiologic studies have reported that cancer survivors have a relatively low risk of developing dementia, but the mechanisms underlying that inverse relationship are mostly unknown. The Granulin (GRN) gene single nucleotide variant rs5848 T allele is associated with increased risk of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-Aging). The T allele is also associated with lower expression of the cognate protein progranulin (PGRN), which is a mitogen implicated in neoplasia. We examined whether the rs5848 variant associated with LATE-NC/HS-Aging pathology and cancer in the same cohort. This study leveraged genotype data from the Alzheimer's Disease Genomics Consortium (n = 8121) and the Alzheimer's Disease Sequencing Project (n = 3231), with cancer history and neuropathology data drawn from the National Alzheimer's Coordinating Center. The rs5848 T allele was associated with higher odds of LATE-NC (p < 0.001) and was also associated with lower odds of cancer (p = 0.012). Established TMEM106B, APOE, and BIN1 risk alleles for Alzheimer's disease showed no associations with cancer, implying that the GRN-related associations could not be completely explained by selection bias in the study sample. The finding of a specific allele with opposite correlative impact on cancer risk and dementia-related pathology has potential therapeutic implications.

Humans↗

PubMed2024

Further description of the phenotypic spectrum of neuronal ceroid lipofuscinosis type 11.

PURPOSE: Ceroid lipofuscinosis type 11 (CLN11) is a very rare disease, being reported in only 13 unrelated families so far. Further reports are necessary to comprehend the clinical phenotype of this condition. This article aims to report 9 additional cases of CLN11 from 9 unrelated Latin American families presenting with relatively slow disease progression. METHODS: This was a retrospective observational study including patients with CLN11. Patients were identified through an active search for granulin precursor gene (GRN) pathogenic variants across the entire database of next-generation sequencing of a commercial laboratory and by contacting attending physicians to check for clinical and radiologic findings compatible with a neuronal ceroid lipofuscinosis phenotype. RESULTS: Nine CLN11 patients from unrelated families were evaluated. Age of onset varied between 3 to 17 years. The most common findings were visual impairment, cerebellar ataxia, seizures, myoclonus, and cognitive decline. One patient had a previously unreported finding of cervical, perioral, and tongue myoclonus. Most of the patients were able to walk unassisted after an average of 14.2 years (SD 4.76 y) from disease onset. CONCLUSION: We describe 9 new cases of a very rare type of neuronal ceroid lipofuscinosis (CLN11) from Latin America with a recurrent p.(Gln257ProfsTer27) and a novel p.(Cys83Ter) nonsense variant. Our findings suggest that a slowly progressive neuronal ceroid lipofuscinosis might be a clue for the diagnosis of CLN11.

Humans↗

PubMed2025

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Humans↗