Research in neurodegenerative diseases: progranulin peripheral levels as a screening tool for the identification of subjects with PGRN mutations in a Portuguese cohort
Maria Rosário Almeida, Inês Baldeiras, Maria Helena Ribeiro, Beatriz Santiago, Cristina Machado, João Massano, Joana Guimarães, Catarina Resende Oliveira, Isabel Santana (FMUC, CNC)
Progranulin (PGRN) mutations are associated with different clinical phenotypes, including Frontotemporal Lobar Degeneration (FTLD), Corticobasal Syndrome (CBS) and Alzheimer's Disease (AD). As all pathogenic PGRN mutations identified so far cause disease through happloinsufficiency, progranulin levels determination has been proposed as a reliable method to identify mutation carriers. The aim of the present study concerns the evaluation of the accuracy of peripheral progranulin levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort.

Serum progranulin levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendents of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit. Low progranulin levels were detected in 7 individuals (five bvFTD, one CBS and one still clinically unaffected) that constituted the group of the null progranulin mutation carriers previously identified in our molecular diagnosis laboratory. The pathogenic mutations found, consisted of four insertion-deletions, causing frameshifts resulting in premature stop codons, three of which were novel. In addition, a normal progranulin level was found in a patient harbouring a novel missense variant. For this novel ELISA kit, we established a progranulin cut-off level that identified with 100% accuracy the pathogenic mutation carriers. This study supports the use of a novel assay for the determination of progranulin levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload, and should be extended to other clinical phenotypes than bvFTD, and to apparently sporadic cases.
Financiado por Fundos FEDER através do Programa Operacional Factores de Competitividade – COMPETE 2020 e por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia no âmbito do projecto Estratégico com referência atribuida pelo COMPETE: POCI-01-0145-FEDER-007440

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