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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.583?C 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.583?C, 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.583?C mutation.

SUBMITTER: Pierce SB

PROVIDER: S-EPMC3215002 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Pierce Sarah B SB Spurrell Cailyn H CH Mandell Jessica B JB Lee Ming K MK Zeligson Sharon S Bereman Michael S MS Stray Sunday M SM Fokstuen Siv S MacCoss Michael J MJ Levy-Lahad Ephrat E King Mary-Claire MC Motulsky Arno G AG

Proceedings of the National Academy of Sciences of the United States of America 20111031 45

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-xylulos ...[more]

PMID: 22042873

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

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

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