PREVALENT AND RARE MUTATIONS AMONG GAUCHER PATIENTS

Sequence analysis of gcs cDNA (encoding glucocerebrosidase) or genomic fragments originated from Gaucher patients revealed novel mutations. Two rare mutations were found in a type-2 non-Jewish Gaucher patient: a G → A transition (Gly325 → Arg) at nucleotide (nt)_5306 of the active gene and a T → G transversion (Cys342 → aGly) at nt 5357. These mutations were not found in any other patient. A G → C transversion (Asp409 → His) at nt 5957 was identified in tow non-Jewish patients, and was designated TL. Two recombinant alleles were found. One recombinant allele designated recTL contained four single-nt mutations. These mutations included: (1) a G → C transversion at nt 5957 (Asp409 → His) (the TL mutation); (2) a T → C transition at nt 6433 (Leu444 → Pro) creating NciI site (NciI mutation); (3 a G → C transversion at nt 6468 (Ala456 → Pro; 456 mutation); and (4) a G → C transversion at amino acid (aa) 460 (nt 6482), not with any aa change. Sequence analysis indicated that at least part of exon 9, intron 9 and exon 10 of the recombinant gene derived from the pseudogene. The other recombinant gene, designated recNciI, contained a mutation at aa 444 (NciI mutation), and mutations 456 and 460 described above; at least exon 10 of this gene originated from the pseudogene. We hypothesize that the presence of the pseudogene close to the active gene causes transfer of mutations into the active gene via gene conversion or nonhomologous recombination, thus accounting for the high frequency of mutations observed in the gcs gene. © 1990.