DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish‐Polish‐Russian descent

Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non‐neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the gluco cerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genomic DNA nucleotide position 6683) from a Gaucher disease patient of Jewish‐Polish‐Russian descent with type 1 Gaucher disease. It is a G→A transition in exon 11 that results in 496 Arg→ 496 His of glucocerebrosidase. This missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease Hph I. We have developed a simple method to detect the presence of this mutation by using Hph I restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A→G transition at cDNA nucleotide position 1226 which creates an Xho I cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease. Since it was also postulated that mutation 1226 in the homozygous form will usually result in a good prognosis, we speculate that the orthopedic complications and the unusual presence of glomerulosclerosis in this patient may be attributable to the mutation at nucleotide 1604. This speculation will require a description of more patients with this mutation for confirmation.