GRN, the gene coding for the progranulin (PGRN) protein, was recognized as a 
gene linked to frontotemporal lobar degeneration (FTLD). The first mutations 
identified were null mutations giving rise to haploinsufficiency. Missense 
mutations were subsequently detected, but only a small subset has been 
functionally investigated. We identified missense mutations (C105Y, A199V, and 
R298H) in FTLD cases with family history and/or with low plasma PGRN levels. The 
aim of this study was to determine their pathogenicity. We performed functional 
studies, analyzing PGRN expression, secretion, and cleavage by elastase. GRN 
C105Y affected both secretion and elastase cleavage, likely representing a 
pathogenic mutation. GRN A199V did not alter the physiological properties of 
PGRN and GRN R298H produced only moderate effects on PGRN secretion, indicating 
that their pathogenicity is uncertain. In the absence of strong segregation data 
and neuropathological examinations, genetic, biomarker, and functional studies 
can be applied to an algorithm to assess the likelihood of pathogenicity for a 
mutation. This information can improve our understanding of the complex 
mechanisms by which GRN mutations lead to FTLD.