A cluster of progranulin C157KfsX97 mutations in Southern Italy: clinical characterization and genetic correlations

Abstract

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases displaying high clinical, pathologic, and genetic heterogeneity. Several autosomal dominant progranulin (GRN) mutations have been reported, accounting for 5%–10% of FTLD cases worldwide. In this study, we described the clinical characteristics of 7 Italian patients, 5 with a diagnosis of frontotemporal dementia behavioral variant and 2 of corticobasal syndrome (CBS), carrying the GRN deletion g.101349_101355delCTGCTGT, resulting in the C157KfsX97 null mutation, and hypothesized the existence of a founder effect by means of haplotype sharing analysis. We performed plasma progranulin dosage, GRN gene sequencing, and haplotype sharing study, analyzing 10 short tandem repeat markers, spanning a region of 11.08 Mb flanking GRN on chromosome 17q21. We observed shared alleles among 6 patients for 8 consecutive short tandem repeat markers spanning a 7.29 Mb region. Therefore, also with this particular mutation, the elevated clinical variability described among GRN-mutated FTLD cases is confirmed. Moreover, this is the first study reporting the likely existence of a founder effect for C157KfsX97 mutation in Southern Italy.