Six novel ?-galactosidase gene mutations in Brazilian patients with GM1-gangliosidosis

Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population

“…R59H is a known mutation reported previously in GM1-gangliosidosis patients in other parts of the world: two homozygous siblings from Italy (patients 2.1 and 2.2 in [8,9]) and eight aVected subjects from Brazil (patients 1-8 in [15]). To test the possibility of a common origin, we reexamined the family history of the aVected siblings diagnosed in Italy and established that the parents were Gypsy migrants from the Balkans.…”

“…Analysis of GLB1 polymorphisms showed that these patients were homozygous for the same haplotype as observed in Gypsy disease chromosomes from Bulgaria (Table 1). In Brazil, R59H accounts for over 20% of GM1-gangliosidosis alleles (in 9 out of the 40 disease chromosomes reported in [15]), with diVerent polymorphic haplotypes suggesting a recurrent mutation. Our comparison with the haplotypes inferred from the published Brazilian data showed that the ancestral Gypsy haplotype is identical to the less common haplotype of Brazilian R59H alleles (referred to as "Brazilian 2" in the Table below; present in patients 3, 6, and 7 in Table 2 of [15]), supporting the possibility of a founder mutation spreading to South America with the Gypsy diaspora.…”

“…In Brazil, R59H accounts for over 20% of GM1-gangliosidosis alleles (in 9 out of the 40 disease chromosomes reported in [15]), with diVerent polymorphic haplotypes suggesting a recurrent mutation. Our comparison with the haplotypes inferred from the published Brazilian data showed that the ancestral Gypsy haplotype is identical to the less common haplotype of Brazilian R59H alleles (referred to as "Brazilian 2" in the Table below; present in patients 3, 6, and 7 in Table 2 of [15]), supporting the possibility of a founder mutation spreading to South America with the Gypsy diaspora. Balkan Roma, a substantial proportion of the Gypsy community of Brazil, reached South America in the late 19th-early 20th century, as part of the large migration wave out of Romania after the abolition of Gypsy slavery [18].…”

“…Sequencing analysis of the GLB1 gene on chromosome 3p21.33 [13,14] was performed using primers as described [15] and ABI Big Dye 3.1. chemistry. The products were run on an ABI 377 DNA Analyzer, with Sequence Navigator used for data analysis.…”

“…The products were run on an ABI 377 DNA Analyzer, with Sequence Navigator used for data analysis. Intragenic GLB1 polymorphisms L10P (rs7637099), L12L (rs7614776), R521C (rs4302331), and S532G (a putative mutation/polymorphism not listed in SNP databases) [15] were analysed by sequencing exons 1 and 15. Population screening for the R59H mutation was done in a panel of 413 anonymous controls, representing diVerent Gypsy sub-isolates in Bulgaria [16,17].…”