The new research focused on a form of HIBM in Iranian-Jewish families, which is caused by a specific mutation in the GNE gene known as M712T. Numerous other GNE mutations can cause HIBM and occur in populations worldwide. At this time, there is no treatment available for any type of HIBM.

In their search for potential HIBM treatments, the researchers drew upon previous evidence that impairment of the enzymes that promote sialic acid production causes low sialic acid levels in muscle proteins. They hypothesized that a compound called N-acetylmannosamine, or ManNAc, a sugar that is naturally converted to sialic acid, might have an impact on the muscle weakness caused by HIBM.

To help test that hypothesis, Dr. Huizing and her colleagues created a transgenic mouse model in which M712T GNE gene mutation was introduced into a strain of mice. However, the researchers were surprised to find that, instead of developing adult-onset muscle disease as expected, the transgenic mice developed a kidney condition that caused them to die just a few days after birth. When the researchers supplemented the diets of pregnant transgenic mice with ManNAc, sialic acid production improved in the fetuses, and they were born with markedly improved kidneys.

We were surprised that the HIBM mutation had such a detrimental impact on kidney function in the transgenic mice, said Dr. Huizing. Structural elements in the kidney that are important for filtering waste from the blood in these animals were severely impaired and we linked this to sialic acid deficiency. This outcome demonstrates the significance of the ability of the body to synthesize sialic acid for kidney development and function.

NHGRI Clinical Director William Gahl, M.D., Ph.D., who w
'"/>

Contact: Raymond MacDougall
macdougallr@mail.nih.gov
301-402-0911
NIH/National Human Genome Research Institute
1-Jun-2007