Mutations in progranulin explain atypical phenotypes with variants in MAPT

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Presenilin-1 (PSEN1) and MAPT gene mutations are known causes of autosomal dominant Alzheimer's disease and Frontotemporal dementia linked to chromosome 17 (FTDP-17), respectively.
• However, some Frontotemporal Dementia (FTD) cases with ubiquitin-positive, tau-negative inclusions were previously linked to PSEN1 and MAPT mutations.

Discussion:

• This study investigates the genetic basis of FTD with ubiquitin-positive, tau-negative inclusions.
• The research clarifies the role of MAPT variants in these specific FTD cases, identifying them as rare benign polymorphisms.
• The findings highlight Progranulin (PGRN) as the primary causative gene in these instances.

Key Insights:

• MAPT variants previously associated with FTD and ubiquitin-positive, tau-negative inclusions are confirmed as rare benign polymorphisms.
• Mutations in Progranulin (PGRN) are identified as the cause of FTD with ubiquitin-positive, tau-negative inclusion pathology.
• This research refines the genetic understanding of FTD subtypes.

Outlook:

• Further research can explore the precise mechanisms by which PGRN mutations lead to tau-negative FTD pathology.
• Investigating the prevalence of PGRN mutations in diverse FTD populations is warranted.
• This work may guide diagnostic strategies for FTD with specific pathological features.