Fucosidosis: four new mutations and a new polymorphism.

Fucosidosis is a rare lysosomal storage disease due to a nearly complete deficiency of alpha-L-fucosidase (EC 3.2.1.51). In this study, all 8 exons of the alpha-L-fucosidase structural gene (FUCA-1) were amplified by PCR methods, and the amplified products were subcloned and sequenced. Five patient groups with fucosidosis were selected according to their ethnic backgrounds and haplotypes for RFLPs in FUCA-1. Four presumptive disease causing mutations were detected: 1) A major deletion of DNA containing the last two exons of FUCA-1 in two Algerian siblings. 2) A G to T mutation in exon 6 resulting in an in-frame termination codon (E375X) in eight Hispanic patients from Colorado and New Mexico. 3) A G to A mutation (G60D) in exon 1 in four Italian patients and in three related French-American (Cajun) patients. This G60D mutation creates a unique site for AflIII. 4) A frameshift mutation resulted from a two-base deletion in exon 2 (K151fs) in an Italian patient. This deletion obliterates a unique BstXI site and creates a new BpmI site, and was found in only this patient and in only one allele. The rationale for proposing these defects as disease causing mutations includes pedigree analysis and the predicted consequences of each defect upon the activity and the concentration of the enzyme. An A to G transition (Q281R) in exon 5 was found to be present in homozygous form in affected patients and also in normal subjects; it appears to be a newly identified polymorphism. It causes a charge change and may be responsible for the electrophoretic variant phenotype of fucosidosis.(ABSTRACT TRUNCATED AT 250 WORDS)