2,8-Dihydroxyadenine urolithiasis associated with partial deficiencies of adenine phosphoribosyltransferase (APRT) has been found only among Japanese families. All Caucasian patients with the same lithiasis are completely deficient in this enzyme. Partially purified APRT from one of the Japanese families with the lithiasis associated with a partial deficiency of APRT had a reduced affinity for 5-phosphoribosyl-1-pyrophosphate (PRPP). In the present investigations, we have shown that this characteristic is common in mutant enzymes from all the four separate Japanese urolithiasis families associated with partial APRT deficiencies so far tested. The mutant enzymes also had several other characteristics in common including increased resistance to heat in the absence of PRPP and reduced sensitivity to the stabilizing effect of PRPP. These data suggest that these families have a common mutant allele (APRT*J) at the APRT gene locus.
"Type I APRT deficiency (complete deficiency in vivo or in vitro), on the other hand, has been found in patients from many different countries. Type I patients are homozygotes or compound heterozygotes for a variety ofnull alleles collectively designated APRT*QO (Fujimori et al. 1985; Hidaka et al. 1987). To date, three different QO mutant alleles have been identified (Hidaka et al. 1987; Sahota et al. 1990). "
[Show abstract][Hide abstract] ABSTRACT: We have completely sequenced the adenine phosphoribosyltransferase (APRT) gene from each of six patients--five (I-V) from Iceland and one (VI) from Britain. Cases I and II shared a common ancestor six and seven generations ago, and cases I and V shared a common ancestor seven generations ago, but cases III and IV were unrelated to the above or to each other, over seven generations. Genomic DNA was amplified by PCR, subcloned into M13mp18, and sequenced. Genomic and PCR-amplified DNAs were also analyzed by restriction-enzyme digestion and Southern blotting. The same missense mutation was identified in all six patients. This mutation leads to the replacement of asp (GAC) by val (GTC), at amino acid position 65. The gene sequences from all patients were otherwise identical to our wild-type sequence. The homozygous nature of the mutation was confirmed by sequencing the PCR product directly. All six patients were homozygous for the 1.25-kb TaqI RFLP. The Icelandic patients were also homozygous for the 8-kb SphI RFLP, but the British patient was heterozygous at this site. These studies suggest that a founder effect is likely to be responsible for APRT deficiency in the Icelandic population. The finding of the same mutation in a patient from Britain suggests that this mutation may have originated in mainland Europe.
The American Journal of Human Genetics 01/1992; 49(6):1306-11. · 10.93 Impact Factor
"All heterozygotes for type I APRT deficiency (genotype APRT*1/APRT*QO, where APRT*1 is the wild-type allele) that have been examined so far have shown no evidence for any clinical or biochemical abnormality (Fox et al. 1977; Dean et al. 1978; Simmonds et al. 1989). Type II heterozygotes with the genotype APRT*1/APRT*J also appear to be clinically and biochemically normal (Fujimori et al. 1985; Kamatani et al. 1987). In the present report we describe a Japanese patient with DHA lithiasis who has functional APRT activity in cultured lymphoblasts. "
[Show abstract][Hide abstract] ABSTRACT: All reported cases of 2,8-dihydroxyadenine (DHA) lithiasis have been due to functional homozygous deficiency of adenine phosphoribosyltransferase (APRT). Here we describe the first case of DHA lithiasis in a patient who has functional APRT activity in cultured lymphoblasts. The patient is heterozygous for Japanese-type (type II) APRT deficiency as demonstrated by starch-gel electrophoresis and DNA sequence analysis. We also demonstrate the use of starch-gel electrophoresis for differentiation between the type II mutant enzyme and the wild-type enzyme.
The American Journal of Human Genetics 06/1991; 48(5):983-9. · 10.93 Impact Factor
"The other heterozygote studied (H2) has a germinally mutated allele, APRT*QO. Although the precise mutation of this allele has not been defined, the family study clearly indicated that this germinally defective allele codes for a complete APRT deficiency (Fujimori et al. 1985). Southern blot analysis of the genomic DNA indicated that both H1 and H2 had a genotype of 2.1 kb/2.8 kb for the common TaqI RFLP (fig. "
[Show abstract][Hide abstract] ABSTRACT: An accurate diagnosis of heterozygotes for autosomal recessive disorders with unknown mutations can be difficult. Using a unique phenomenon occurring in vivo, we designed a method for the diagnosis of heterozygotes for adenine phosphoribosyltransferase (APRT) deficiency which makes way for a qualitative distinction between normal and heterozygous subjects. We cultured peripheral blood mononuclear cells with 2,6-diaminopurine, an APRT-dependent cytotoxin, to search for in vivo mutational cells. Fifteen putative heterozygotes examined were found to possess such mutant cells at rather high frequencies; thus, a false negative diagnosis is unlikely. The analysis of genomic DNA in 82 resistant clones from two of the heterozygotes clarified that 64 (78%) had lost the germinally intact alleles. Thirteen members of APRT-deficient families were examined; eight proved to be heterozygotes. Among 425 individuals from two separate residential areas of Japan, two heterozygotes were found. The authenticity of the heterozygosity was validated by two separate methods for the two heterozygotes; hence, a false positive diagnosis can be ruled out. Our data showed a calculated heterozygote frequency of 0.47% (95% confidence limits; 0.05%-1.7%), a value compatible with that (1.2%) calculated from data concerning the incidence of 2,8-dihydroxyadenine urolithiasis. This novel genetic approach for identifying heterozygotes is now being tested to search for other enzyme deficiencies in humans.
The American Journal of Human Genetics 04/1991; 48(3):552-62. · 10.93 Impact Factor
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