Serum progranulin level in a subject carrying ‘predicted’ pathogenic PGRN mutation p.R564C

Although most of the known pathogenic mutations in the progranulin gene (PGRN) are null mutations leading to a reduction in the serum PGRN protein levels, missense mutations also have been identifi ed in patients with frontotemporal lobar degeneration and in patients with Alzheimer disease. Among these, p.R564C mutation was identifi ed in a late-onset AD patient with a reduced serum PGRN level. However, recently, we found the p.R564C mutation in a healthy control subject raising doubts whether this is a pathogenic mutation. In this report, we measured the serum PGRN levels in 20 subjects without the p.R564C mutation and in one subject with the p.R564C mutation, to determine whether the p.R564C mutation is associated with reduced serum PGRN levels. We found that the serum PGRN level in the subject with the p.R564C mutation was not reduced compared to the subjects without the p.R564C mutation. Our result reiterates that p.R564C may not be a pathogenic mutation. Neurology Asia 2011; 16(4) : 343 – 344 Address correspondence to: Beom S. Jeon, Department of Neurology, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Korea. Tel: +82-2-2072-2876, Fax: +82-2-3672-7553, e-mail: [email protected] INTRODUCTION The PGRN gene encodes for progranulin, which undergoes proteolytic cleavage giving rise to a family of peptides, the granulins. Progranulin acts as a growth factor in a variety of tissues and is highly expressed in the central nervous system (CNS), but its exact role in the CNS is unknown. Mutations in PGRN have been associated with frontotemporal lobar degeneration (FTLD) and related neurodegenerative disorders. Most of the known PGRN mutations are null mutations leading to a reduction in PGRN protein levels, which might be causally related to neurodegeneration in FTLD. In this regard, serum PGRN levels have been proposed as a reliable biomarker for the detection of PGRN null mutations. Besides null mutations, PGRN missense mutations have been identifi ed in patients with FTLD and in patients with Alzheimer disease (AD). Some of these missense mutations are presumed to be potentially pathogenic because of the partial loss of mutant PGRN proteins and, in agreement with this, reduced serum PGRN levels have been demonstrated in the carriers of some of the missense mutations. Among these, the p.R564C mutation was identifi ed in a late-onset AD patient with a reduced serum PGRN level. However, recently, we found a p.R564C mutation in a healthy control subject raising doubts whether this is a pathogenic mutation. In this report, we measured the serum PGRN levels in subjects without the p.R564C mutation and in one subject with the p.R564C mutation, to determine whether the p.R564C mutation is associated with reduced serum PGRN levels.