Progranulin variability has no major role in Parkinson disease genetic etiology

Background: Different loss-of-function mutations were identified underlying PGRN haploinsufficiency in patients with frontotemporal lobar degeneration. PGRN mutations were also identified in other neurodegenerative brain diseases such as amyotrophic lateral sclerosis and Alzheimer disease, though their biologic contribution to these diseases remains elusive. Because of its apparent role in neuronal survival, we argued that PGRN might also contribute to Parkinson disease (PD) pathogenesis. Methods: We screened PGRN exons for mutations in 255 patients with PD and 459 control individuals by direct genomic sequencing. Genetic association of PGRN with risk for PD was assessed using single nucleotide polymorphisms (SNPs) across the gene. Results: In patients we identified four missense mutations of which p.Asp33Glu and p.Arg514Met were absent in control individuals. Single SNP and haplotype analyses did not detect significant associations with PD. Conclusions: Our results do not support a major role for PGRN in the genetic etiology of Parkinson disease (PD). At this stage and in the absence of functional data, it remains unclear whether p.Asp33Glu and p.Arg514Met are biologically relevant to PD pathogenesis in the mutation carriers.

[1]  K. Sleegers,et al.  Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia , 2007, Human mutation.

[2]  B. Boeve,et al.  Mutations in progranulin explain atypical phenotypes with variants in MAPT. , 2006, Brain : a journal of neurology.

[3]  S. Melquist,et al.  Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. , 2006, Human molecular genetics.

[4]  C. Broeckhoven,et al.  Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme , 2003, Journal of medical genetics.

[5]  A. Munnich,et al.  Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype , 2007, Human mutation.

[6]  P. Cras,et al.  Case–control study of environmental risk factors for Parkinson's disease in Belgium , 2002, European Journal of Epidemiology.

[7]  Julie S Snowden,et al.  Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. , 2008, Brain : a journal of neurology.

[8]  C. Broeckhoven,et al.  Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update , 2008, Human mutation.

[9]  K. Sleegers,et al.  Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease , 2008, Neurology.

[10]  J. Morris,et al.  Neuropathologic Heterogeneity in HDDD1: A Familial Frontotemporal Lobar Degeneration With Ubiquitin-positive Inclusions and Progranulin Mutation , 2007, Alzheimer disease and associated disorders.

[11]  C. Haass,et al.  Missense Mutations in the Progranulin Gene Linked to Frontotemporal Lobar Degeneration with Ubiquitin-immunoreactive Inclusions Reduce Progranulin Production and Secretion* , 2008, Journal of Biological Chemistry.

[12]  J. Hardy,et al.  Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis–frontotemporal dementia phenotypes , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[13]  C. Broeckhoven,et al.  Progranulin locus deletion in frontotemporal dementia , 2008, Human mutation.

[14]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[15]  J. Morris,et al.  HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin‐positive, tau‐negative inclusions caused by a missense mutation in the signal peptide of progranulin , 2006, Annals of neurology.

[16]  C. van Broeckhoven,et al.  A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. , 2006, Brain : a journal of neurology.

[17]  C. Broeckhoven,et al.  Progranulin genetic variability contributes to amyotrophic lateral sclerosis , 2008, Neurology.

[18]  C. Jack,et al.  Prominent phenotypic variability associated with mutations in Progranulin , 2009, Neurobiology of Aging.

[19]  K. Sleegers,et al.  Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. , 2007, Archives of neurology.

[20]  Marc Cruts,et al.  Loss of progranulin function in frontotemporal lobar degeneration. , 2008, Trends in genetics : TIG.

[21]  P. Pietrini,et al.  Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation , 2007, Neurology.

[22]  P. Heutink,et al.  Progranulin mutations in Dutch familial frontotemporal lobar degeneration , 2007, European Journal of Human Genetics.

[23]  Andrew King,et al.  A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. , 2008, Brain : a journal of neurology.

[24]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[25]  G. Schellenberg,et al.  A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. , 2007, Brain : a journal of neurology.