On the Age of the Most Prevalent Gaucher Disease–Causing Mutation, N370S

Abstract

To the Editor:We have recently described a common origin for the most prevalent mutation (N370S) observed among Gaucher disease (GD) patients of Ashkenazi Jewish (AJ) and Spanish descent (Diaz et al. 1999xGaucher disease: the N370S mutation in Ashkenazi Jewish and Spanish patients has a common origin and arose several thousand years ago. Diaz, A, Montfort, M, Cormand, B, Zeng, BJ, Pastores, GM, Chabas, A, Vilageliu, L et al. Am J Hum Genet. 1999; 64: 1233–1238Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all References1999). We also estimated the age of this mutation, using a formula described by Risch et al. (1995bxGenetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Risch, N, DeLeon, D, Ozelius, L, Kramer, P, Almasy, L, Singer, B, Fahn, S et al. Nat Genet. 1995b; 9: 152–159Crossref | PubMed | Scopus (299)See all References1995b). Unfortunately, as R. Colombo pointed out in a recent report (Colombo 2000xAge estimate of the N370S mutation causing Gaucher disease in Ashkenazi Jews and European populations: a reappraisal of haplotype data. Colombo, R. Am J Hum Genet. 2000; 66: 692–697Abstract | Full Text | Full Text PDF | PubMed | Scopus (22)See all References2000), there was an error in the formula presented in the original publication that was never rectified. In a reply (Risch et al. 1995axITD in Ashkenezi Jews—genetic drift or selection? In reply. Risch, N, DeLeon, D, Fahan, S, Ozelius, L, Breakfield, X, Kramer, P, Almasy, L et al. Nat Genet. 1995a; 11: 14–15CrossrefSee all References1995a) to criticisms raised by Zoossmann-Diskin (1995xITD in Ashkenazi Jews—genetic drift or selection?. Zoossmann-Diskin, A. Nat Genet. 1995; 11: 13–14Crossref | PubMed | Scopus (4)See all References1995), Risch et al. made no mention of an error in the formula. The continued application of the formula by researchers who may not be well versed in the field may lead to repeated mistakes if the error remains uncorrected. We apologize for our failure to recognize the error, but we are pleased that it has been identified by Colombo, who had no difficulty in re-estimating the age of the mutation, using our data. This reappraisal indicates that the N370S mutation may have occurred between the 11th and 13th centuries or even in the 10th century, considering 30 years per generation as suggested recently by Tremblay and Vezina (2000xNew estimates of intergenerational time intervals for the calculation of age and origin of mutations. Tremblay, M and Vezina, H. Am J Hum Genet. 2000; 66: 651–658Abstract | Full Text | Full Text PDF | PubMed | Scopus (117)See all References2000). This new estimated date for the mutation suggests that it occurred (or entered) the AJ population after the separation of the Ashkenazi and Sephardic Jewish traditions, which would be consistent with the apparent absence of this mutation among Sephardic patients. Using a totally different approach based on mutation detection in healthy Roman Jews, Oddoux et al. (1999xMendelian diseases among Roman Jews: implications for the origins of disease alleles. Oddoux, C, Guillen-Navarro, E, Ditivoli, C, Dicave, E, Cilio, MR, Clayton, CM, Nelson, H et al. J Clin Endocrinol Metab. 1999; 84: 4405–4409Crossref | PubMedSee all References1999) also got to the conclusion that the N370S is an old mutation. Further information on the origin of a mutation could be provided from the length of the chromosomal region noted with linkage disequilibrium (LD) and the strength of the LD. In this case, the data can be used to determine whether the N370S mutation had a Jewish or non-Jewish origin. The 3.2-cM region in LD in AJ (Diaz et al. 1999xGaucher disease: the N370S mutation in Ashkenazi Jewish and Spanish patients has a common origin and arose several thousand years ago. Diaz, A, Montfort, M, Cormand, B, Zeng, BJ, Pastores, GM, Chabas, A, Vilageliu, L et al. Am J Hum Genet. 1999; 64: 1233–1238Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all References1999) seems to be shorter in Spanish chromosomes, as the flanking marker D1S2624 is in LD among AJ, whereas it is not in Spanish GD patients. Moreover, LD values are stronger in AJ than in Spanish chromosomes. These observations suggest that the mutation was introduced later in the AJ population, a statement that is independent of the actual age of the mutation. However, these results should be taken with caution because of the small number of Spanish chromosomes included in the study. Further work would be necessary to settle this issue which, to date, remains an open question.