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Newswise Research in zebrafish has helped identify the cause of an unknown genetic disorder affecting a boy and two of his uncles, scientists report in an article published October 14 in the journal GENETICS.

The findings demonstrate the growing importance of zebrafish as laboratory models of rare diseases. Such models allow geneticists to make sense of the deluge of candidate disease genes being uncovered by advances in sequencing technologies. Although rare diseases are uncommon individually, together they affect as many as 25 million people in the United States.

The project began when a young boy with a puzzling constellation of symptoms was referred to medical geneticist Susan Brooks of the Rutgers Robert Wood Johnson Medical School. The child was suffering from delayed development, recurrent fevers, seizures, and slow growth. He also had poor head growth, resulting in microcephaly, or head size much smaller than healthy children his age. Two of the boys uncles shared many of these symptoms, suggesting that the mysterious disorder might be caused by a recessive mutation on the X-chromosome. Such "X-linked" mutations can be carried by both males and females, but with few exceptions, cause symptoms only in males.

Using this clue, the scientists tracked down a mutation carried only by the affected males and their mothers, within a gene called RPL10 located on the X-chromosome. This gene encodes part of the ribosome, which is a central piece of the molecular machinery that translates the genetic code into proteins.

But although they now had a candidate mutation, they couldnt tell if it had actually caused the disorder or if it was merely one of the many harmless DNA variants that litter the genomes of every family.

For more common genetic diseases, scientists can confirm that a candidate mutation causes a disease by identifying other families with the same mutation and same symptoms. But this variant was unique. Although a few mutations in other parts of the RPL10 gene had been found previously, those who carried them did not show clinical signs similar to this familys disorder. So, the team turned to the next best option for studying very rare variants they tested the effect of the mutation in a model organism.

Brooks enlisted the help of a Duke University team led by Erica Davis from the Center for Human Disease Modeling, with most of the zebrafish experimental work performed by then-undergraduate Alissa Wall. They showed that dampening expression of the zebrafish rpl10 gene caused the animals to develop significantly smaller heads in other words, they were displaying the fish version of microcephaly.

When they replaced the suppressed zebrafish gene with the human version, the fish heads developed to a normal size. But when the researchers tried the same trick using the mutated variant of the human RPL10 gene, it didnt work. In other words, the change in DNA sequence prevented RPL10 from functioning properly. These findings strongly suggested that the mutation is also responsible for microcephaly in the males from the original family.

See the article here:
For One Family, Zebrafish Help Provide Genetic Answers

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