Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration

Abstract

<b>Background: </b> Mutations in the progranulin gene (<i>PGRN</i>) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles leading to a 50% loss of progranulin transcript. <b>Methods: </b> Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. We enrolled affected (n = 6) and unaffected at risk members (n = 73) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation; additionally, we included subjects affected by sporadic/familial FTLD (n = 65), controls (n = 75), and a family carrying the tau P301L mutation. The presence of mutations in <i>PGRN</i> and <i>MAPT</i> genes was investigated by direct sequencing of exonic and flanking intronic regions. Progranulin plasma and CSF levels were measured using ELISA. <b>Results: </b> We demonstrated that progranulin protein is strongly reduced (up to 3.93-fold) both in plasma and CSF of affected and unaffected subjects carrying mutations in progranulin gene (PGRN Leu271LeufsX10 and Q341X). We established a plasma progranulin protein cutoff level of 74.4 ng/mL that identifies, with specificity and sensitivity of 100%, mutation carriers among unaffected subjects. In FTLD, values ≤110.9 ng/mL give a specificity of 92.8% and a sensitivity of 100% for <i>PGRN</i> mutations. <b>Conclusions: </b> We propose the dosage of plasma progranulin as a useful tool for a quick and inexpensive large-scale screening of carriers of progranulin mutations and for monitoring future treatments that might boost the level of this protein. <b>GLOSSARY: </b><b>FTD</b> = frontotemporal dementia; <b>FTLD</b> = frontotemporal lobar degeneration; <b>PPA</b> = primary nonfluent aphasia.