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 transmitt ed as an autosomal recessive trait. Three clinical forms of Gaucher di sease have been described: type 1, non-neuronepathic; type 2, acute ne uronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the glucocerebrosidase gene and identified an unc ommon mutation in nucleotide position 1604 (genomic DNA nucleotide pos ition 6683) from a Gaucher disease patient of Jewish-Polish-Russian de scent with type 1 Gaucher disease. It is a G-->A transition in exon 11 that results in (496)Arg-->(496)His of glucocerebrosidase. This misse nse mutation is present in the heterozygous form and creates a new cle avage site for the endonuclease HphI. We have developed a simple metho d to detect the presence of this mutation by using HphI restriction fr agment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is a n A-->G transition at cDNA nucleotide position 1226 which creates an X hoI cleavage site after PCR mismatch amplification. The presence of th is 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 d iagnosed as having type 1 Gaucher disease. Since it was also postulate d that mutation 1226 in the homozygous form will usually result in a g ood prognosis, we speculate that the orthopedic complications and the unusual presence of glomerulosclerosis in this patient may be attribut able to the mutation at nucleotide 1604. This speculation will require a description of more patients with this mutation for confirmation. ( C) 1994 Wiley-Liss, Inc.