Novel insertion mutation in a non-Jewish Caucasian type 1 Gaucher disease patient
AMERICAN JOURNAL OF MEDICAL GENETICS(1997)
摘要
Gaucher disease is the most prevalent lysosomal storage disorder, It is autosomalrecessive, resulting in lysosomal glucocerebrosidase deficiency. Three clinical forms of Gaucher disease have been described: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic), We performed PCR-thermal cycle sequence analysis of glucocerebrosidase genomic DNA and identified a novel mutation in a non-Jewish type 1 Gaucher disease patient. It is a C insertion in exon 3 at cDNA nucleotide position 122 and genomic nucleotide position 1626, This mutation causes a frameshift and, subsequently four of the five codons immediately downstream of the insertion were changed while the sixth was converted to a stop codon, resulting in premature termination of protein translation. The 122CC insertion abolishes a Cac81 restriction endonuclease cleavage site, allowing a convenient and reliable method for detection using RFLP analysis of PCR- amplified glucocerebrosidase genomic DNA, The mutation in the other Gaucher allele was found to be an A-->G substitution at glucocerebrosidase cDNA nucleotide position 1226 that so far has only been reported among type 1 Gaucher disease patients, Since mutation 122CC causes a frameshift and early termination of protein translation, it most likely results in a meaningless transcript and subsequently no residual glucocerebrosidase enzyme activity, We speculate that mutation 122CC may result in a worse prognosis than mutations associated with partial activity, When present in the homozygous form, it could be a lethal allele similar to what has been postulated for the other known insertion mutation, 84GG. Our patient, who is a compound heterozygote 122CC/1226G, has moderately severe type 1 Gaucher disease. Her clinical response to Ceredase(R) therapy that began 31 months ago has been favorable, though incomplete. (C) 1997 Wiley-Liss, Inc.
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关键词
Gaucher disease,glucocerebrosidase,ceredase therapy,mutation,PCR
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