A novel progranulin mutation causing frontotemporal lobar degeneration with heterogeneous phenotypic expression

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease impacting behavior and cognition.
• Phenotypic heterogeneity is observed in FTLD patients.
• Progranulin (GRN) plays a role in FTLD pathogenesis.

Purpose of the Study:

• To investigate the genetic basis of FTLD in an Italian family with phenotypic heterogeneity.
• To identify novel mutations in the progranulin gene (GRN).
• To explore the role of genetic factors in disease onset and presentation.

Main Methods:

• Analysis of the progranulin gene (GRN) in affected individuals.
• Identification of mutations using genetic sequencing.
• mRNA analysis to confirm mutation effects.
• Haplotype analysis (MAPT) to assess disease modifiers.

Main Results:

• A novel frame-shift mutation (T278SfsX7) was identified in the GRN gene.
• mRNA analysis confirmed a null effect of the identified mutation.
• Patients were homozygous for the H1 MAPT haplotype, a known disease modifier.
• Low plasma progranulin levels were observed in affected individuals.

Conclusions:

• The identified GRN mutation leads to reduced progranulin levels and contributes to FTLD.
• The H1 MAPT haplotype may influence the early onset of FTLD.
• Plasma progranulin measurement is a valuable diagnostic tool for GRN null mutations in dementia work-up.