Frontotemporal dementia: identification of a splicing variant at +1 of Exon 8 in the GRN gene with normal plasma progranulin levels
Résumé
Background-aim
Frontotemporal Dementias (FTD) are the second leading cause of dementia in individuals under 65. They primarily manifest as behavioral disturbances (disinhibition, irritability) and phasic disorders (primary progressive aphasia, semantic dementia). Hereditary FTD with autosomal dominant transmission is mainly caused by nonsense, frameshift, or splicing variants of the GRN gene, which encodes progranulin. Abnormal transcripts are degraded by nonsense-mediated decay (NMD), leading to
Methods
Analysis of a panel of 13 genes responsible for FTD revealed the heterozygous splicing variant c.835+1G>A in the GRN gene, located in intron 8. The SpliceAI prediction software for splicing variants indicated a decrease in the splicing score of the consensus donor site in intron 8 and an increase in the splicing score of a cryptic donor site located in exon 8 at position c.772. This variant was also described in two other FTD patients, one of whom had normal progranulin levels.
Results
Transcript analysis, conducted using lymphocyte cultures treated with and without emetine (NMD inhibitor), revealed a deletion corresponding to 20 amino acids of the protein (Lys259 to Val279) and the insertion of a methionine at position 259, resulting in a shortened in-phase protein (p.Lys259_Val279delinsMet). Since progranulin levels were normal in the patient, the protein is secreted. Among the 20 deleted amino acids, 3 belong to the granulin B domain, and the cleavage site between
Conclusions
Considering the obtained results, the presence of three unrelated FTD patients carrying this splicing variant, and its absence in general population databases (1 in 251,311 in gnomADv2), the splicing variant c.835+1G>A in the GRN gene can be classified as probably pathogenic according to the ACMG criteria.