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Narcolepsy may be caused by a mutation in the prepro-orexin gene
By Sharon Guynup

A German research team has associated a rare genetic mutation in the prepro-orexin gene with narcolepsy symptoms.

This discovery builds on other recent breakthroughs in the understanding of narcolepsy, a condition marked by uncontrollable episodes of deep sleep and involuntary muscle relaxation. A recent study using narcoleptic breeds of Doberman pinschers, Labrador retrievers, and orexin knockout mice connected the sleep disorder with abnormalities in the orexin neurotransmitter system. Another investigation showed disturbed orexin transmission in humans—orexin A was absent in seven out of nine narcolepsy patients.

Martin Gencik, of the Department of Molecular Human Genetics at St. Josef-Hospital, Ruhr-University in Bochum, and his team took these findings one step further. They conducted a study to determine if there were genetic causes of the disease that might be associated with orexin. They screened the prepro-orexin gene, which encodes orexin, for mutations. Gencik's team discovered that some of the narcoleptic patients carried a variant of the gene (3250T).

In most cases, however, human narcolepsy appears to be inherited as a multifactorial trait, unlike dog and mice models. The 3250T allele may predispose individuals to the condition in combination with other mutations or environmental factors. Also, narcoleptic traits in animal models are inherited in an autosomal recessive manner. But the German researchers found that in humans, all patients carrying the 3250T allele were typed heterozygous, which suggests dominant influence. "It is conceivable that the 3250T allele acts directly or via linked sequence variants to influence the expression of orexin negatively by diminished transcription activity or decreased RNA stability," the researchers write in Neurology.

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Gencik, M. et al. A prepro-orexin gene polymorphism is associated with narcolepsy. Neurology 56, 115-117 (January 9, 2001).

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