Pedigree analysis of alpha-L-fucosidase gene mutations in a fucosidosis family.

Fucosidosis is an autosomal recessive lysosomal storage disease resulting from absence of alpha-L-fucosidase activity. Lymphoid cell lines from two siblings with fucosidosis and a healthy individual (control) had alpha-L-fucosidase mRNA of normal size (2.3 kb) but the level of alpha-L-fucosidase mRNA in the patients' cells was reduced. cDNA was prepared and amplified from alpha-L-fucosidase mRNA of lymphoid cells of the patients, their carrier parents, and the control. Direct DNA sequencing demonstrated three mutations in the fucosidosis family. One mutation, C1282-->T, changed the codon (CAA) for Gln-422 to a stop codon (UAA). This mutation was heterozygous (C and T) in the patients and their father and independently confirms an earlier report (J. Mol. Neurosci. (1989) 1, 177). Another mutation, C247-->T, changed the codon (CAG) for Gln-77 to a stop codon (UAG) and was heterozygous (C and T) in the patients and their mother. The third mutation, A860-->G, changed the codon CAG for Gln-281 to the codon (CGG) for Arg and was heterozygous (A and G) in the patients but homozygous in their father. alpha-L-Fucosidase activity in cells of the father was 37% of controls indicating that homozygosity of the A860-->G mutation did not cause an absence of alpha-L-fucosidase activity and fucosidosis. This mutation probably results in a normal polymorphic variant of alpha-L-fucosidase. It is proposed that the combination of the C247-->T mutation on the maternal allele of the alpha-L-fucosidase gene and the C1282-->T mutation on the paternal allele caused fucosidosis in the patients.