A Mutation in the 5 %26apos;-UTR of GRN Gene Associated with Frontotemporal Lobar Degeneration: Phenotypic Variability and Possible Pathogenetic Mechanisms

作者：Puoti Gianfranco; Lerza Maria Cristina; Ferretti Maria Giulia; Bugiani Orso; Tagliavini Fabrizio; Rossi Giacomina^*

来源：Journal of Alzheimer's Disease, 2014, 42(3): 939-947.

DOI：10.3233/JAD-140717

• Frontotemporal lobar degeneration
• GRN
• haploinsufficiency
• mutation
• phenotype
• progranulin

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%26apos; splice site A %26gt; G in the 5%26apos;-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%26apos; splice site A %26gt; G mutation widens the GRN regions affected by null mutations, including the 5%26apos;-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.

• 出版日期2014