Association of the Variant Cys139Arg at GRN Gene to the Clinical Spectrum of Frontotemporal Lobar Degeneration

J Alzheimers Dis. 2014;40(3):679-85.

Piaceri I1, Pradella S1, Cupidi C2, Nannucci S1, Polito C3, Bagnoli S1, Tedde A1, Smirne N2, Anfossi M2, Gallo M2, Bernardi L2, Colao R2, Maletta R2, Bruni AC2, Sorbi S1, Nacmias B1.

  • 1Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
  • 2Centro Regionale di Neurogenetica, ASP Catanzaro, Lamezia Terme (CZ), Italy.
  • 3Department of Clinical Pathophysiology, Nuclear Medicine Division, University of Florence, Florence, Italy.



Background: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer’s disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them.

Objective: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD.

Methods: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples.

Results: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured
in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein.

Conclusion: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD.

KEYWORDS: Cys139Arg; frontotemporal dementia; mutation; plasma; progranulin

PMID: 24503614



The identified DNA variation is a pathogenic mutation or a polymorphism? Answering this question is very difficult for geneticists in relation to an unknown DNA variation.

Until to date, the absence of the genetic change in 100 chromosomes from 50 healthy subjects was considered sufficient to classify a variation as a pathogenic mutation.

The majority of Progranulin (PGRN) mutations correlating with Frontotemporal dementia (FTD) phenotype cause a premature termination of the protein or affect the protein secretion (Figure 1A, B) and still today some genetic variants are reported as variations of unclear pathogenic nature (Figure 1C). However, we cannot exclude the possibility that they have a role in the disease mechanism.

Our study investigated the role of the PGRN variant Cys139Arg in three different families.

The changed residue is located within a Granulin peptide (GRN F) and is conserved among different species, suggesting the possibility that it might be important for GRN F function. In fact, the Cys139Arg genetic variant affects the first of two consecutive cysteine residues destroying one of the Cys-bridges and interfering with protein folding (Figure 1C). Tests in vitro have demonstrated that cysteine mutations affect the proteolytic process of PGRN and reduce the production of particular GRNs (Wang et al, Journal of Neurochemistry 2010, 112: 1305–1315).

The functional role of both PGRN and Granulin (its proteolytic products, GRNs) proteins is poorly understood, making difficult to determine the pathogenicity of variants that affect only one of the GRNs. However, our study, investigating three different families carrying the Cys139Arg, add new important information in order to clarify the role of this variant in the disease.

We provide evidence that the Cys139Arg in PGRN gene could be a disease-causing mutation being associated to different clinical phenotypes.

Different research centers worldwide are involved in a collaborative consortium, GENFI (, to track the evolution of the genetic form of FTD and its associated disorders from their earliest stages. To date, only patients carrying mutations that affect the production of progranulin and its secretion are included in these studies excluding the possibility to patients carrying potential pathogenic variants the opportunity to participate in clinical trials. For this reason it is very important to clarify the role of the variants with possible pathogenic nature, not only to better address patients and their families in significant decisions for their future, but also to carry out complete clinical trials for disease-modifying therapies.


Fig 1. Overview of wild type and mutant Progranulin.


Schematic representation of the genomic structure of PGRN gene (top), progranulin protein (PGRN) and the Proteolytic cleavage of PGRN (bottom).
The black numbered boxes in the genomic structure indicate the non-coding exon 1 and the 3′ untranslated region; the blue numbered boxes indicate coding exons 2 to 13. The colored lettered heptagons in PGRN refer to the individual granulin domains.
(A) After secretion, the wild type progranulin can be complete cleaved in 8 granulin peptides (GRN A-G and paragranulin P).
(B) Example of pathogenic mutation: a mutation on exon 12 (C.1420_1421delTG; p.Cys474LeufsX37) resulting in a reduced secretion of the PGRN protein and in an incomplete cleavage. The mutant progranulin can be cleaved in 6 granulin peptides (GRN D and GRN E are lost).
(C) Mutation on exon 5 (c.415T>C, p. Cys139Arg) and its result in the cleavage of PGRN. After secretion, the full-length protein cannot be completely cleaved. The mutant progranulin can be cleaved in 7 granulin peptides (GRN F is lost).