Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. (June 2004) Severe subacute G(M2) gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mmRNA. American Journal of Medical Genetics Part A, 127A (2). pp. 158-166. ISSN 0148-7299
Abstract
We have characterized the molecular basis of beta-hexosaminidase A (HEX A) deficiency in a patient ascertained through an ophthalmologic examination that revealed cherry red spots on his retina. The absence of neurological deficit in this child until 3(3)/(4) years of age indicated residual HEX A must be present. Three HEXA mutations, 10T > C (S4P) and 972T > A (V324V) on the maternal allele, and 1A > T (M1L) on the paternal allele were identified. The effects of the amino acid substitutions on HEX A expressed in COS-7 cells were analyzed; as expected, no HEX A activity was associated with the M1L mutation but surprisingly, the S4P mutation resulted in 59% of the HEX A activity expressed by the wild type cDNA. The effect of the S4P change was much less than that of another HEXA mutation, G269S, associated with an adult onset form Of G(M2) gangliosidosis. This indicated that the S4P change was not the cause of disease and suggested that one of the mutations on the maternal allele, 10T > C or 972T > A, had its effect at the mRNA level. This was confirmed by Northern blot analysis that showed only 7% of the normal level of HEXA mRNA in proband fibroblasts. Analysis of the residual mRNA by RT/PCR and sequencing revealed normal transcripts from both the maternal and paternal allele, as well as a low abundance aberrant transcript from the maternal allele. Sequencing of this aberrant transcript revealed a new exon 8 donor site created by the 972T > A mutation that resulted in a 17 bp deletion and destabilization of the resulting abnormal transcript. The remaining normal mRNA produced from the 972T > A allele must account for the delayed onset of clinical symptoms in this child. (C) 2004 Wiley-Liss, Inc.
| Item Type: | Paper |
|---|---|
| Additional Information: | ISI Document Delivery No.: 821MR Times Cited: 3 Cited Reference Count: 34 |
| Uncontrolled Keywords: | Tay-Sachs disease G(M2) gangliosidosis HEXA beta-hexosaminidase aberrant splicing splice donor mutation TAY-SACHS-DISEASE BETA-HEXOSAMINIDASE ALPHA-SUBUNIT GM2 GANGLIOSIDOSIS LYSOSOMAL STORAGE STOP MUTATIONS ASHKENAZI JEWS ADULT FORM GENE SUBSTITUTION |
| Subjects: | diseases & disorders > congenital hereditary genetic diseases organism description > animal behavior > vision |
| CSHL Authors: | |
| Depositing User: | CSHL Librarian |
| Date: | June 2004 |
| Date Deposited: | 17 Jan 2012 18:02 |
| Last Modified: | 20 Apr 2012 20:32 |
| URI: | https://repository.cshl.edu/id/eprint/22516 |
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