Molecular genetic study of a Japanese family with Lesch-Nyhan syndrome: a point mutation at the consensus region of RNA splicing (HPRTKeio).

Complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) causes Lesch-Nyhan syndrome. A single nucleotide substitution of G to T at the 3'-end of intron 3 in the splicing consensus region has been identified in one allele of the HPRT gene from a mother predicted to be a heterozygous Lesch-Nyhan carrier. Utilizing a BfaI restriction site which was lost in the mutation as an indicator, family study showed that the mother and her only daughter were heterozygotes but the mother's sister did not have the mutant allele. The mutation generated splicing error and resulted in two types of abnormal mRNA. The major altered mRNA, named Type I, skipped the exon 4 and is predicted to produce a protein deleted of 22 amino acid residues. The other, Type II, having a 9-bp deletion at the 5'-end of exon 4, can result in a protein lacking 3 amino acids, from codon 107 to 109.