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Mutations in the keratin 8 gene linked to liver disease
Edward R. Winstead

Mutations in the keratin 8 gene may predispose individuals to liver disease and may account for some of the unexplained cases of liver disease, according to a study published in The New England Journal of Medicine. Ten percent of liver transplant patients have an illness of unknown origin, or cryptogenic liver disease.

"We propose that mutations in the keratin 8 gene or the keratin 18 gene predispose patients to liver disease at least in part by interfering with the normal reorganization of keratin filaments…that occurs in response to physiological and nonphysiological stimuli," the researchers write. A mutation in the keratin 18 gene had previously been linked to liver disease of unknown origin.

Nam-On Ku, of the Division of Gastroenterology at Stanford University School of Medicine, in Palo Alto, California, led the study. Keratins comprise a group of 20 'filament' proteins. The keratin 8 and keratin 18 genes are primarily expressed in the liver, pancreas, and intestine.

The researchers identified 5 patients with mutations at one of two locations in the keratin 8 gene. Another patient had a mutation in the keratin 18 gene. The six patients had liver diseases of unknown origin. The study included 55 patients with cryptogenic liver disease, 98 patients with 'known' liver diseases, and 86 controls.

Stress, such as heat, caused defects in cells with the mutations, the researchers found. For example, heat caused the collapse of filaments in cells with the Y53H mutation; filaments in normal cells reorganize when stressed.

The researchers speculate that the physiological consequences of the mutations in the keratin 8 gene are related to "the dynamic nature and reorganization that keratins undergo during cellular events, including mitosis and stress."

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Ku, N.-O. et al. Keratin 8 mutations in patients with cryptogenic liver disease. N Engl J Med 344, 1580-1587 (May 24, 2001).

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