Novel Tay-Sachs disease mutations from China

Abstract

We describe three HEXA mutations associated with infantile Tay-Sachs disease (TSD) in three unrelated nonconsanguineous Chinese families. Novel mutations were found in two of these families. The third is a previously reported mutation (G-->A transition at nt 1444) (Nakano et al., 1988). Direct sequencing of PCR products identified a novel insertion of an A after nt 547 in family 1. This change generates an early termination codon 6 bp downstream from the insertion site. Allele-specific oligonucleotide hybridization confirmed homozygosity in the proband. Single strand conformational polymorphism analysis and direct sequencing of amplified exon 13 revealed a T-->C transition at nt 1453 with the corresponding amino acid substitution W485R in the second family. This mutation creates an Fnu4HI restriction site. The proband is homozygous for this allele. When the site-specific mutagenized alpha cDNA carrying the T-->C transition at nt 1453 was expressed in COS 1 cells hexosaminidase S activity was not detectable above background. A G-->A transition at nt 1444 (exon 13) corresponding to the E482K substitution was found in the third family. This mutation occurs at a CpG dinucleotide. It has been reported in an Italian TSD proband and causes defective intracellular transport of the alpha-subunit from the rough endoplasmic reticulum to the Golgi apparatus.

Role of βArg211 in the Active Site of Human β-Hexosaminidase B

“…Previously reported methods to increase the “signal (from translated human cDNA) to noise (endogenous Hex)” ratios have resulted in values of 30:1 (), 75:1 (), and 50−100:1 ( , ). For purposes of determining if a naturally occurring mutation is neutral or disease-causing, this signal-to-noise level is more than sufficient ( − ). However, this ratio is too low to unequivocally identify a mutation that severely increases K m or one that neutralizes the catalytic acid or base residue present in the active sites of glycosidases.…”

Tay-Sachs disease andHEXA mutations among Moroccan Jews

“…An ASO hybridization assay was developed to detect the G 1444 →A substitution and, as expected, only the DNA from this individual with the migration change in SSCP hybridized with the mutant probe (not shown). This mutation has been described in an Italian family (Nakano et al, 1988) as well as in a Chinese TSD infant (Akalin et al, 1992). The overall results are summarized in Table 1.…”

Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations

“…DNA sequencing technology has shown that TSD is caused by numerous mutations, disproving the myth that its causes were sole. French Canadians and Ashkenazi Jews, for instance, have shown evidence of genetic heterogeneity when it comes to TSD within these populations [ 163 ]. Furthermore, Ashkenazi Jews can have multiple mutations leading to TSD while Moroccan Jews with TSD can display distinct mutations as causes [ 164 ].…”