Original articleA new point mutation (G412 to A) at the last nucleotide of exon 3 of hexosaminidase α-subunit gene affects splicing
Introduction
Tay-Sachs disease is an autosomal recessive sphingolipid storage disease due to a deficiency of the hexosaminidase A (hex A) enzyme. It is a catastrophic disorder and is characterized by accumulation of GM2 ganglioside in the neurons of the cerebral cortex. Clinically, the result is a spectrum of disease states ranging from severe and fatal to mild and chronic. Affected infants do not attain early milestones such as sitting or crawling and lose most cognitive functions by the second year. Mutations at the α-subunit gene of the lysosomal enzyme hex A are responsible for the enzyme deficiency and Tay-Sachs disease [1]. To date 20 splice site mutations out of 87 mutations have been reviewed at the HEX A gene [2]. Previously, five Tay-Sachs mutations that cause infantile type of the disease have been detected in the Turkish population: two point mutations that yield stop codons, one splice site and one deletion mutations [3], [4]. Three of these five mutations are unique to the Turkish population.
In the present study, we report a new mutation at the last nucleotide of exon 3 of hex α-chain gene in a Turkish infant with infantile type of Tay-Sachs disease and its effect on gene expression.
Section snippets
Clinical summary of the patients
Two patients with infantile Tay-Sachs disease were included in this study. The mutation of patient 1 was not detected by single stranded conformational polymorphism (SSCP) analysis.
Identification of the mutation
PCR amplification products of all HEX A exons and flanking sequences were subjected to SSCP analysis. All amplification products produced a pattern of bands that was identical for normal control DNA except for band patterns of exon 3-containing fragments (Fig. 1).
Detection of the mutation in genomic DNA
DNA sequence analysis of exon 3 revealed a transition mutation G412 to A at the last nucleotide of exon 3 (Fig. 2). The patient was homozygote for the mutation.
The effect of the G to A transition mutation at the splice site of exon 3
Discussion
A novel HEX A mutation has been identified in a Turkish infant with acute infantile type Tay-Sachs disease. The exon 3 donor splice site mutation is the second splice site and sixth mutation found in the Turkish population. The other splice site mutation was at the IVS5+1 position of the HEX A gene. In this work, our data indicated that this novel mutation results in a lack of HEX A mRNA by defective splicing. The lack of detectable α-subunit is most likely because of the instability of the
Acknowledgements
This work was supported by Scientific and Technical Research Council of Turkey (TUBITAK) and Deutsche Forschung Gemeinschaft. We thank Dr R. Proia for providing the cDNA clones of human Hex, and Dr Christina Schütte and Dr Julia Bär for their technical assistance.
References (8)
Biochemical consequences of mutations causing the GM2 gangliosidoses
Biochim Biophys Acta
(1999)- et al.
At least six different mutations in Hex A gene cause Tay-Sachs disease among the Turkish population
Mol Genet Metab
(1998) - et al.
The GM2 gangliosidoses
- et al.
Donor splice site mutation in intron 5 of the Hex A gene in a Turkish infant with Tay-Sachs disease
Hum Mutat
(1995)
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