Affiliations: [a] Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Italy | [b] Division of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
Correspondence:
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Correspondence to: Giacomina Rossi, PhD, Division of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy. Tel.: +39 02 2394 4647; Fax: +39 02 2394 2101; E-mail: grossi@istituto-besta.it.
Abstract: Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5–10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5′ splice site A > G in the 5′-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5′ splice site A > G mutation widens the GRN regions affected by null mutations, including the 5′-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.
