© 1993 Oxford University Press
OTHER |
Fucosidosis: four new mutations and a new polymorphism
Department of Neurosciences and Center for Molecular Genetics, University of California San Diego, La Jolla, CA 92093-0634, USA 1Department of Medical Genetics, University of Antwerp U.I.A Belgium 2Stratagene Cloning Systems 11099 North Torrey Pines Road, La Jella, CA 92037 3Section on Molecular Neurogenetics, Clinical Neuroscience Branch, National Institute of Mental Health Bethesda, MD 20892, USA
* To whom correspondence should be addressed
Received November 25, 1992; Revised January 27, 1993; Accepted January 27, 1993
Fucosidosis is a rare lysosomal storage disease due to a nearly complete deficiency of 
-L-fucosidase (EC 3.2.1.51
[EC]
). In this study, all 8 exons of the -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 Afl III. 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. This polymorphism is inherited concordant with the RFLP PvuII—BglI haplotype 2 – 2, 2 – 2. The 4 new mutations identified here comprise 70% of alleles of the 25 fucosidosis patients in our study.