NOVEL INSERTION MUTATION IN A NON-JEWISH CAUCASIAN TYPE-1 GAUCHER-DISEASE PATIENT

Gaucher disease is the most prevalent lysosomal storage disorder, It i s autosomalrecessive, resulting in lysosomal glucocerebrosidase defici ency. Three clinical forms of Gaucher disease have been described: typ e 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (suba cute 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 exo n 3 at cDNA nucleotide position 122 and genomic nucleotide position 16 26, This mutation causes a frameshift and, subsequently four of the fi ve codons immediately downstream of the insertion were changed while t he sixth was converted to a stop codon, resulting in premature termina tion of protein translation. The 122CC insertion abolishes a Cac81 res triction endonuclease cleavage site, allowing a convenient and reliabl e method for detection using RFLP analysis of PCR- amplified glucocere brosidase genomic DNA, The mutation in the other Gaucher allele was fo und 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 t ermination of protein translation, it most likely results in a meaning less transcript and subsequently no residual glucocerebrosidase enzyme activity, We speculate that mutation 122CC may result in a worse prog nosis 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 pati ent, 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) 19 97 Wiley-Liss, Inc.