Monday, November 7, 2011

Ashkenazi Jews and pentosuria, an inherited disorder once mistaken for diabetes

Pentosuria occurs almost exclusively in Ashkenazi Jews, a population that has traditionally married within its own religious and ethnic group. Pentosuria causes high levels of a five-carbon sugar, xylulose, in urine and blood. Pentosuria is inherited as an autosomal recessive condition: a person has to inherit a causative gene sequence from both parents to have the disorder. By 2002, researchers had identified the gene that codes for the enzyme that normally rids the body of excess xylulose. Still no mutations were identified in pentosuria. However, in the course of sequencing DNA, the UW genomics laboratory of Dr. Mary-Claire King serendipitously discovered a deletion in this gene in an individual of Ashkenazi Jewish background. It was hypothesized that, because the mutated gene led to a protein missing about 50 amino acids, it couldn't produce the right sugar-busting enzyme. Genetic analysis of DNA samples from particular Jewish families led to the discovery of two different DCXR mutations linked to loss of function of the xylulose-breaking enzyme. In nine unrelated people with pentosuria, six had one type of mutation, one had the other, and two had both. None had the active enzyme in question in their blood cells, and all had high levels of xylulose in their blood. This confirmed the relationship between the mutations and the metabolic error. Studies of the frequency of the two mutations in 1,067 Ashkenazi Jews showed that one mutation is more common than the other and suggested that pentosuria occurs in about 1 in 3,330 people of this ancestry. The frequency of the two DCXR mutations causing pentosuria in Ashkenazi Jews follows a pattern of other rare recessive mutations in this population. The Israeli National Genetic Database shows that for most of the Jewish genetic diseases, including Tay Sachs disease, Canavan syndrome, maple syrup urine disease and Gaucher disease, two or more mutations in the same gene have been found, with one mutation more common than the other, according to the researchers. For conditions like cystic fibrosis and a certain inherited hearing loss that are common in Jews and other groups, two or more mutations in the same gene have been discovered, with the more common mutation found throughout Europe and the less common one specific to the Ashkenazi Jewish population. Other studies have suggested that many of the founder mutations for Ashkenazi Jewish genetic diseases date back to three time periods: the expansion of the Jewish population in the Middle East about 100 generations ago, the entry of the Jewish population into Central Europe about 50 generations ago, and their movement into Lithuania and the Pale of the Settlement about 12 generations ago. Although previous studies of pentosuria indicate that it is entirely benign, animal studies on the DCXR enzyme suggest that mutations that result in a loss of enzyme function could play a role in kidney damage. If so, patients with both pentosuria and diabetes could be more susceptible to diabetic kidney disease.

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