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ARTICLES: W. C. Nichols, N. Pankratz, D. K. Marek, M. W. Pauciulo, V. E. Elsaesser, C. A. Halter, A. Rudolph, J. Wojcieszek, R. F. Pfeiffer, T. Foroud For the Parkinson Study Group–PROGENI Investigators Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset Neurology 2009; 72: 310-316 [Abstract] [Full text] [PDF]

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Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset

Ellen Sidransky, Ted Samaddar, Nahid Tayebi   (23 February 2009)

Reply from the authors

William C. Nichols, Nathan Pankratz, Tatiana Foroud   (23 February 2009)

Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset 23 February 2009
Ellen Sidransky, National Human Genome Research Institute 35 Convent Drive 1A213, Bethesda, MD 20892, Ted Samaddar, Nahid Tayebi Send Correspondence to journal: Re: Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset sidranse{at}mail.nih.gov Ellen Sidransky, et al.	Nichols et al. further examine the association between mutations in glucocerebrosidase (GBA) gene and Parkinson disease (PD) but the data may be misleading. [1] Studies in diverse cohorts indicate that mutations in GBA confer an increased risk for the development of parkinsonism. [2] This study on familial PD examined 1325 cases from 566 multiplex families and 359 controls, concluding that the unbiased frequency of GBA alterations in patients was 12.6% versus 5.3% in controls. However, the screening methods and definition of GBA mutations may not be accurate. First, the authors sequenced a subset of 96 subjects identified by their non-parametric lod score using markers surrounding GBA. Without sequencing another sample that did not meet these criteria, they have not shown that using this shortcut is more likely to yield mutations. Moreover, control subjects were not sequenced. In non-Ashkenazi Jewish cohorts, sequencing of GBA is essential to accurately ascertain mutation frequency. For example, our sequencing of 188 controls in the Coriell plates used in this study, NDPT002 and NDPT006, identified two N370S alleles, one L444P, two rare alleles E388K and D443N, and five with polymorphism E326K, demonstrating that the genotypes of the controls reported in this study are incomplete. Furthermore, in Table 2, the exonic designations are incorrect and the first novel splice site change was previously described. [3] Secondly, the authors considered subjects with E326K and T369M as mutation carriers. Both alleles have been commonly reported in controls, and among subjects with Gaucher disease they appear in cis with a second mutation. [4,5] Moreover, their frequency varies among ethnicities. Based on other published studies, the reported frequency of these alleles among both cases and controls is high, and a much larger ethnically defined cohort should be evaluated. In Table 3, the majority of the GBA mutants identified in both cases and controls were E326K and T369M. Removing these samples, the mutation rate for the three other mutant alleles screened was 4.1% in cases versus 1.1% in controls which is consistent with other studies screening for only a few GBA mutations. [2] The observation that GBA mutations are common in familial PD is important and serves to further broaden the phenotypic spectrum of parkinsonism associated with mutations in this gene. However, for genetic counseling purposes, a more accurate assessment of mutation frequency in cases and controls is imperative. References 1. Nichols WC, Pankratz N, Marek DK et al. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology 2008;0: 01.wnl.0000327823.81237.d1v1 2. Ziegler SG, Eblan MJ, Gutti U,et al. Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol Genet Metab 2007;91:195-200. 3. Dominissini S, Buratti E, Bembi B, Baralle M, Pittis MG. Characterization of two novel GBA mutations causing Gaucher disease that lead to aberrant RNA species by using functional splicing assays. Hum Mutat 2006;27:119. 4. Park JK, Tayebi N, Stubblefield BK et al. The E326K mutation and Gaucher disease: Mutation or polymorphism? Clin Genet 2002;61:32-34. 5. Walker JM, Lwin A, Tayebi N, LaMarca ME, Sidransky E. Glucocerebrosidase mutation T369M appears to be another polymorphism. Clin Genet 2003;63:237-238. Disclosure: The authors report no disclosures.
Reply from the authors 23 February 2009
William C. Nichols, Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue, 1469 TCHRF, Cincinnati OH 45140, Nathan Pankratz, Tatiana Foroud Send Correspondence to journal: Re: Reply from the authors bill.nichols{at}cchmc.org William C. Nichols, et al.	We thank Dr. Sidransky et al. for their comments and would like to provide further clarification. We did not conclude that the unbiased estimate of GBA mutations in patients was 12.6% versus 5.3% in controls. We stated that these numbers represent the unbiased estimate of five previously reported GBA variants (three pathogenic and two polymorphic variants). Since we did not sequence GBA in all patients and any controls, we cannot determine an unbiased estimate of all GBA variants in familial PD. This was noted in the Discussion. [1] Our previous genome-wide linkage analyses provided an opportunity to prioritize GBA screening in patients from families demonstrating increased sharing of alleles in the GBA region.[6,7] Nine GBA variants were identified in the 96 sequenced probands (21.9%). It is unlikely that sequencing 96 random probands without evidence of linkage to chromosome 1q would yield such a high proportion. Sidransky et al. sequenced a subset of the controls used in our study. Through sequencing, they identified two rare variants that were not among the five known variants for which we screened. They identified variants in 5.3% of their controls (10/188), the same proportion we reported, suggesting that screening for only the five known variants missed only a small number of rare variants. In GenBank, there are five different gene structures for GBA based on different mRNA variants. We used sequence NM_001005741, representing transcript variant 2 encoded by a 12 exon gene as others have done. [8] Based on this, our exon designations are correct. Sidransky et al. are correct that one of our four novel variants was published previously. We apologize for the oversight. The majority of GBA variants identified were E326K and T369M. Removing these from our analysis, the frequency for the three screened pathogenic alleles was 4.1% (cases) versus 1.1% (controls), consistent with other studies screening for only a few GBA mutations. We neither stated, nor implied, that our results were inconsistent with other studies. Except for one instance, changes in GBA were labeled variants, not mutations; the E326K and T369M variants were designated ‘polymorphic variants’. We demonstrated that carrying either of these two variants significantly lowered age of PD onset. Coupled with their combined overrepresentation in cases versus controls (p=0.02), we concluded it was prudent to include and report them in the analyses. We encourage analyses of additional samples to further validate the association of PD and GBA. References 6. Pankratz N, Nichols WC, Uniacke SK, et al. Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. Am J Hum Genet 2002;71:124-135. 7. Pankratz N, Nichols WC, Uniacke SK, et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet 2003;12:2599-2608. 8. Clark LN, Ross BM, Wang Y, et al. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 2007;69:1270-1277. Disclosure: The authors report no disclosures.