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Two Disorders Reveal New Complexities In Body's Use Of Genes

Johns Hopkins Medicine

ohns Hopkins researchers studying the genetic changes underlying some cancers and genetic disorders have shown how a single gene can play a role in two very different and distinct inherited disorders, a heart rhythm disturbance and a rare growth ailment.

The key is a genetic phenomenon called imprinting that selectively silences one of the two copies of a gene that every person receives--either the copy from their father or the copy from their mother.

In a paper in this month's Nature Genetics, Hopkins scientists including Maxwell Lee, Ph.D., an instructor of medicine, and Andrew Feinberg, M.D., King Fahd professor of medicine, report on imprinting and the gene KVLQT-1, identified by another research group and linked to an inherited disorder of the heartbeat, long Q-T syndrome.

They found new connections between KVLQT-1 and Beckwith Weidemann Syndrome (BWS), a genetic imprinting disorder. Babies born with BWS are unusually large, have differences in tongue and ear formation and are at an increased risk for childhood tumors.

Curious about how a gene clearly linked to heart rhythm could also be involved in a growth disorder, they took a closer look at KVLQT-1 to see if it was imprinted.

"We found that KVLQT-1 is imprinted nearly everywhere you look in the body," Feinberg says, "but it's usually not imprinted in the cells of the heart."

This selective imprinting may explain why changes to the gene have one effect in the heart and another elsewhere in the body, he says.

Imprinting errors can lead to unchecked growth and possibly to cancer. Normally, though, imprinting helps the body differently use the maternal and paternal copies of genes.

Feinberg and others have previously shown that three genes related to BWS are located in a spot on chromosome 11, that these genes are imprinted, and that imprinting of these genes is disrupted in BWS patients.

The new study revealed that KVLQT-1 is found in the same area of chromosome 11 and contains many BWS "breakpoints," spots where gene damage linked to BWS often occurs.

It's possible, Feinberg notes, that all four genes are imprinted in some coordinated fashion.

"We have several genes that can be part of a disease, and they're probably therefore part of the same genetic or biochemical pathway," says Feinberg.

Other authors were Ren-Ju Hu and Laura Johnson. This research was funded by a grant from the National Institutes of Health.

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