Elsevier

Neurobiology of Aging

Volume 29, Issue 3, March 2008, Pages 427-435
Neurobiology of Aging

A novel deletion in progranulin gene is associated with FTDP-17 and CBS

https://doi.org/10.1016/j.neurobiolaging.2006.10.028Get rights and content

Abstract

In the last decade familial frontotemporal dementia (FFTD) has emerged as a distinct clinical disease entity characterized by clinical and genetic heterogeneity.

Here, we provide an extensive clinical and genetic characterization of two Italian pedigrees presenting with FFTD (FAM047: 5 patients, 5 unaffected; FAM071: 4 patients, 11 unaffected). Genetic analysis showed a conclusive linkage (LOD score for D17S791/D17S951: 4.173) to chromosome 17 and defined a candidate region containing MAPT and PGRN genes. Recombination analysis assigned two different disease haplotypes to FAM047 and FAM071. In affected subjects belonging to both families, we identified a novel 4 bp deletion mutation in exon 7 of PGRN gene (Leu271LeufsX10) associated with a variable clinical presentation ranging from FTDP-17 to corticobasal syndrome. The age-related penetrance was gender dependent.

Both mutations in MAPT and PGRN genes are associated with highly variable clinical phenotypes. Despite the profound differences in the biological functions of the encoded proteins, it is not possible to define a clinical phenotype distinguishing the disease caused by mutations in MAPT and PGRN genes.

Introduction

Frontotemporal dementia (FTD; MIM 600274) is a heterogeneous condition characterized at onset by prominent behavioral disturbances, affective disorders, impairment in language, and poor executive function (Neary et al., 1998, The Lund and Manchester Groups, 1994).

Linkage analyses of large pedigrees indicated that loci at chromosomes 3, 9, 16 and 17 are associated with familial FTD (FFTD) (Brown et al., 1995, Hosler et al., 2000, Rademakers et al., 2002, Ruddy et al., 2003). Extrapyramidal features are variably present in FTD patients: a number of families in which FTD is inherited as an autosomal dominant trait have been shown to be linked to chromosome 17q21 and to present a symptomatology that has led investigators to name the disease “Frontotemporal Dementia and Parkinsonism linked to chromosome 17” (FTDP-17) (Foster et al., 1997). A proportion of FTDP-17 were demonstrated to be caused by mutations in the MAPT gene (MIM 157140) located on chromosome 17 and encoding the microtubule-associated tau protein (Hutton et al., 1998, Ingram and Spillantini, 2002, Poorkaj et al., 1998, Spillantini et al., 1998, Wszolek et al., 2005). Missense and 5′ splice-site mutations in the MAPT gene seem to be responsible for between 2.5 and 14% of all familial FTD cases, although some studies suggest higher proportion depending on the analyzed population (Rademakers et al., 2004, Signorini et al., 2004). Neuropathological studies demonstrated that FTD patients carrying MAPT mutations present neuronal and glial tau deposition (Morris et al., 2001). Interestingly, families where the disease is linked to the region on chromosome 17 but with no pathogenic MAPT mutations, lack tau pathology and show ubiquitin-positive inclusions (Froelich et al., 1997, Lendon et al., 1998, Mackenzie et al., 2006, Rademakers et al., 2002, Rosso et al., 2001, van der Zee et al., 2006). The absence of MAPT mutations in many familial cases suggested that FFTD could be caused by mutations in a different gene.

It has been recently demonstrated that tau negative ubiquitin-positive FFTD is caused by mutations in progranulin gene (PGRN, MIM 138945) located on chromosome 17q21 (Baker et al., 2006, Cruts et al., 2006, Gass et al., 2006). Progranulin is a 593 amino acid secreted glycoprotein composed of 7.5 tandem repeats of highly conserved motifs of 12 cysteines, which can be proteolytically cleaved to form a family of 6-kDa peptides called granulins (Zhu et al., 2002); progranulin is a growth factor involved in the regulation of multiple processes including tumorigenesis, wound repair, development and inflammation (Bateman and Bennett, 1998, Bhandari et al., 1992, Diaz-Cueto et al., 2000, He and Bateman, 2003).

Here, we report linkage data, according to which the disease locus is mapping to chromosome 17q21 in two Italian pedigrees affected by familial frontotemporal dementia: the two candidate genes (MAPT and PGRN) located in this locus were analyzed.

Section snippets

Subjects

Patients underwent clinical and neurological examination at the Memory Clinic of the IRCCS “Centro San Giovanni di Dio-Fatebenefratelli” in Brescia, Italy.

Clinical diagnosis of patients affected by FTD, corticobasal syndrome (CBS) and Alzheimer disease (AD) was made according to international guidelines (Boeve et al., 2003, Litvan et al., 1997, McKhann et al., 1984, The Lund and Manchester Groups, 1994). The family history was determined by collection of the Family History Questionnaire

Families description

Family FAM047 presented a positive history of FTD and CBS in seven members (three females, four males) spanning through three generations, with an inheritance pattern suggesting an autosomal dominant trait. The proband (III:2) probably inherited the disease from his father (whose mother was affected) and who died at the age of 61 years because of lung cancer. The mean age of disease onset was 67 years (range = 60–71 years). Detailed clinical information was available on five affected members

Discussion

In the last decade, familial frontotemporal dementia has emerged as a distinct clinical disease entity characterized by clinical and genetic heterogeneity.

FTDP-17 caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology: indeed, clinical presentation can differ not only among mutations, but also within a single mutation and even within individual families (Ingram and Spillantini, 2002, van Swieten et al.,

Conflict of interest

Authors declare that no conflicts of interest exist.

Acknowledgments

The authors wish to acknowledge the helpful and generous collaboration of the families. This work was supported by grants RC2006 and 2003/agreement number PS/03/10, Italian Ministry of Health.

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    Accession numbers and URLs for data presented herein are as follows: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/; GDB Human Genome Database, http://gdbwww.gdb.org/.

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