Background: Primary progressive aphasia (PPA) is a language-based dementia characterized by fluent or nonfluent language disorder as its principal feature. Objective: To describe progranulin gene mutations in 2 families with PPA. Design: Report of affected families. Setting: Academic research. Patients: Two families, PPA1 and PPA3, were studied. Genomic DNA was isolated from 3 of 4 siblings in PPA1, from all 3 siblings in PPA3, and from more than 200 control subjects. Main Outcome Measures: All 12 coding exons of the progranulin gene and the 5′ and 3′ untranslated regions were amplified by polymerase chain reaction and were sequenced in both directions using relevant primers. Results: Both affected members of PPA1 for whom DNA was available and both affected sisters of PPA3 had a progranulin gene mutation not found in the unaffected siblings or in the controls. The mutations likely cause a null allele and a reduction in the level of functional progranulin protein. Both affected members of PPA1 with autopsies had frontotemporal lobar degeneration with taunegative ubiquinated inclusions. Conclusions: To our knowledge, these are the only known families in which affected members display phenotypical homogeneity for PPA in the initial stages of the disease. In both families, the disease segregated with progranulin gene mutations. Whether progranulin dysfunction also extends to sporadic PPA and how it affects the initial anatomical specificity of neurodegeneration remain to be determined. ©2007 American Medical Association. All rights reserved.