Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria

Abstract

Pentosuria is one of four conditions hypothesized by Archibald Garrod in 1908 to be inborn errors of metabolism. Mutations responsible for the other three conditions (albinism, alkaptonuria, and cystinuria) have been identified, but the mutations responsible for pentosuria remained unknown. Pentosuria, which affects almost exclusively individuals of Ashkenazi Jewish ancestry, is characterized by high levels of the pentose sugar l -xylulose in blood and urine and deficiency of the enzyme l -xylulose reductase. The condition is autosomal-recessive and completely clinically benign, but in the early and mid-20th century attracted attention because it was often confused with diabetes mellitus and inappropriately treated with insulin. Persons with pentosuria were identified from records of Margaret Lasker, who studied the condition in the 1930s to 1960s. In the DCXR gene encoding l -xylulose reductase, we identified two mutations, DCXR c.583ΔC and DCXR c.52(+1)G > A , each predicted to lead to loss of enzyme activity. Of nine unrelated living pentosuric subjects, six were homozygous for DCXR c.583ΔC , one was homozygous for DCXR c.52(+1)G > A , and two were compound heterozygous for the two mutant alleles. l -Xylulose reductase was not detectable in protein lysates from subjects’ cells and high levels of xylulose were detected in their sera, confirming the relationship between the DCXR genotypes and the pentosuric phenotype. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi Jewish controls was 0.0173, suggesting a pentosuria frequency of approximately one in 3,300 in this population. Haplotype analysis indicated that the DCXR c.52(+1)G > A mutation arose more recently than the DCXR c.583ΔC mutation.

Human DCXR – another ‘moonlighting protein’ involved in sugar metabolism, carbonyl detoxification, cell adhesion and male fertility?

“…Although the enzyme deficiency responsible for essential pentosuria was identified in 1970 (Wang & Van Eys, 1970), the molecular background was resolved only very recently (Pierce et al, 2011). As a recessive trait, pentosuria has almost exclusively been diagnosed among ethnic groups with a history of endogamy, such as the Ashkenazi Jewish population (Lane & Jenkins, 1985), within which the frequency of pentosuria is one in 3300 individuals (Pierce et al, 2011).…”

A Novel l-Xylulose Reductase Essential for l-Arabinose Catabolism in Trichoderma reesei

“…The molecular background of this condition, pentosuria, was recently elucidated. 18 To date, two fungal LXRs have been functionally verified to be involved in l -arabinose catabolism, including the NADH-dependent ALX1 of the yeast Am. monospora (19) and the recently identified NADPH-dependent LxrA of A. niger .…”

“…In humans, LXR deficiency causes pentosuria, a clinically benign condition that results in large amounts of l -xylulose in the urine of such patients. 18 The first fungal l -xylulose reductase, ALX1, was identified in the yeast Ambrosiozyma monospora and, interestingly, is NADH-dependent. 19 Although an enzyme with l -xylulose reductase (LXR1) was described for T. reesei , 20 its functional characterization showed that it is actually a d -mannitol 2-dehydrogenase.…”

Evolutionary molecular medicine

“…The gene frequency in a North America sample is 1.7 percent, meaning that one in 3300 would be homozygotes. There is no known selective benefit from this condition; its only adverse effect was when bearers were mistakenly diagnosed as diabetic, sometimes resulting in hypoglycemia from ill-advised insulin therapy [103]. …”