Gaucher disease: the N370S mutation in Ashkenazi Jewish and Spanish patients has a common origin and arose several thousand years ago.

To the Editor: The identification of highly polymorphic markers, which are widely distributed throughout the human genome, has allowed the mapping of several disease genes. These markers have been used to analyze the origin, in time and place, of the most prevalent mutations for different diseases, such as cystic fibrosis (Morral et al. 1994), idio-pathic torsion dystonia (Risch et al. 1995), hereditary colon cancer (Moisio et al. 1996), factor XI deficiency (Peretz et al. 1997), and myotonic dystrophy (Tishkoff et al. 1998). We present the analysis of the origin of N370S, the most common Gaucher disease (GD) mutation among Ashkenazi Jewish and Spanish patients. The results show that both patient populations share the same ancestral haplotype and that this mutation arose several thousand years ago. GD (MIM 230800), caused by mutations in the glu-cocerebrosidase (GBA) gene, is the most prevalent ly-sosomal storage disease. It is inherited as an autosomal recessive trait, which is particularly frequent in the Ash-kenazi Jewish population, with a disease incidence of ∼1/850 (Beutler and Grabowski 1995). It is also found in other populations, albeit with lower frequency, with It appears that approximately two-thirds of the individuals homozygous for this mutation escape detection because of the very mild clinical manifestation; thus, the N370S frequency in the Ashkenazi Jewish population is higher, ∼90% of all GD mutations (Beutler et al. 1993; Grabowski 1997). This mutation is also frequent in other populations of patients with GD, particularly among Spanish patients, in whom it accounts for 1 40% of the mutant alleles (Cormand et al. 1995, 1998). We have recently mapped the GBA gene in relation to several highly polymorphic markers (Cormand et al. 1997), which were then used to identify a putative ancestral haplotype associated with the N370S mutation in chromosomes from Spanish patients (Cormand et al. 1998). Preliminary studies of a few Argentinian patients with GD, of Ashkenazi Jewish origin, showed that they have the same conserved haplotype as the Spanish patients with GD. This prompted us to perform the present study on DNA isolated from 66 unrelated Ashkenazi Jewish patients with GD of central and eastern European descent living in the United States, who were evaluated at the New York University Medical Center, and 14 Spanish patients with GD who were referred from different hospitals around Spain and enzymatically diagnosed at the Institut de Bioquímica Clínica in Barcelona. Both groups of patients bore the N370S mutation. A …