Common characteristics of mutant adenine phosphoribosyltransferases from four separate Japanese families with 2,8-dihydroxyadenine urolithiasis associated with partial enzyme deficiencies

Abstract

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.

Adenine Phosphoribosyltransferase Deficiency

“…Type I deficiency mainly affects white individuals but has been also reported in people originating from countries worldwide (6,7,15). In type II deficiency, which accounts for most cases in Japan (4), APRT has a reduced affinity for the cosubstrate 5-phosphoribosyl-1-pyrophosphate and the enzyme activity in cell lysates is about 25% of normal values (16). In fact, this classification applies only to in vitro phenomena in cell lysates and has no relevance in cultured cells (17,18) or in vivo.…”

“…In fact, this classification applies only to in vitro phenomena in cell lysates and has no relevance in cultured cells (17,18) or in vivo. This classification has no known clinical significance because the manifestations of the disease are identical in the two types (4,6,7,16).…”

“…The age at diagnosis varies from infancy to older than 70 years (4,6,7,16). The disease can be diagnosed late, either because patients have remained free of symptoms for decades or because it has remained misdiagnosed despite recurrent urolithiasis.…”

“…In the setting of familial screening, it is not unusual to detect complete APRT deficiency in individuals who are totally asymptomatic even as adults (6,7). The first urolithiasis episode may occur during the first few months after childbirth as well as later than the fifth decade ( Figure 2B) (4,6,16). Reddish-brown diaper stains may be observed in infants (7).…”

“…Reddish-brown diaper stains may be observed in infants (7). In both European and Japanese cohorts, several years or even decades sometimes elapsed before the diagnosis was made ( Figure 2C) (6,7,16). Delayed diagnosis is less frequent when symptoms begin in children because urolithiasis is a much less common condition than in adults, which often alerts physicians to investigate the nature of the stone.…”