Three VCP Mutations in Patients with Frontotemporal Dementia

Area of Science:

• Neurogenetics
• Molecular Neurology
• Human Genetics

Background:

• Valosin-containing protein (VCP) mutations are linked to diverse neurological disorders.
• Clinical presentations of VCP-related diseases are heterogeneous, even with identical mutations.
• Frontotemporal dementia (FTD) genetics often involves screening known genes like MAPT, GRN, and C9orf72.

Purpose of the Study:

• To identify novel genetic causes of familial frontotemporal dementia (FTD) in patients negative for common FTD gene mutations.
• To investigate the role of Valosin-containing protein (VCP) gene mutations in frontotemporal dementia (FTD) pathogenesis.
• To expand the understanding of the clinical and pathological spectrum of VCP-related neurodegenerative diseases.

Main Methods:

• Whole exome sequencing was performed on a cohort of 48 familial FTD patients.
• Targeted sequencing was conducted on 37 patients with frontotemporal lobar degeneration with TDP-43 pathology.
• Genetic analysis included screening for known FTD genes and novel VCP mutations, with absence confirmed in controls.

Main Results:

• Two novel (p.Thr262Ser, p.Arg159Ser) and one known (p.Met158Val) VCP mutations were identified in three FTD patients.
• All affected patients presented with behavioral changes, with one also exhibiting semantic deficits.
• Pathological examination revealed TDP-43 inclusions consistent with FTLD-TDP subtype D in VCP mutation carriers.

Conclusions:

• VCP mutations represent a significant, albeit less common, cause of frontotemporal dementia (FTD).
• The identified VCP mutations expand the known clinical heterogeneity associated with VCP-related disorders.
• Genetic modifiers may influence the clinical phenotype in Valosin-containing protein (VCP) mutation carriers, contributing to disease variability.