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Fish provide proof of genetic defect that leads to brain, skull malformations

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Using tiny zebrafish to create, and then reverse, brain and skull malformations provides proof of a genetic defect that might be important for brain and skull development disorders, said researchers at Georgia Health Sciences University.

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Georgia Health Sciences University research fellow Hyung-Goo Kim and Dr. Lawrence C. Layman have discovered that tiny zebrafish can be bred to express a human gene defect that causes the head not to develop properly and then, just by getting the gene, reverse the syndrome and grow normally. Researchers are using genes identified from human patients who suffer the rare craniofacial and brain development disease called Potocki-Shaffer syndrome. They are also looking at potential ways it might be reversed.  EMILY ROSE BENNETT/STAFF
EMILY ROSE BENNETT/STAFF
Georgia Health Sciences University research fellow Hyung-Goo Kim and Dr. Lawrence C. Layman have discovered that tiny zebrafish can be bred to express a human gene defect that causes the head not to develop properly and then, just by getting the gene, reverse the syndrome and grow normally. Researchers are using genes identified from human patients who suffer the rare craniofacial and brain development disease called Potocki-Shaffer syndrome. They are also looking at potential ways it might be reversed.

In a study published Thursday in the American Journal of Human Genetics, the international team of researchers looked at blood samples from two patients with a rare disorder called Potocki-Shaffer syndrome, said Hyung-Goo Kim, the lead author and a research fellow in Dr. Lawrence Layman’s OB/GYN genetics lab at GHSU.

The syndrome can cause intellectual disability, craniofacial abnormalities such as a misshapen or small skull, enlarged openings between bones in the skull and bony outgrowths.

Specific genetic defects have been identified for the bony growths and skull opening problems but not for the other features. Using genetic analysis of the two patients and a third patient identified from the literature, the researchers were able to focus in on a large “breakpoint,” or disruption in the chromosomes of the patients. Within that area, they were able to zero in on a single disrupted gene called PHF21A.

To test whether it really was the gene, the researchers suppressed the equivalent gene in zebrafish to create the skull formation problems and then could “rescue” or reverse the syndrome by giving the protein from the gene.

Though the specific syndrome is rare, intellectual disability and craniofacial problems are not, and the discovery could lend insights into other more common disorders, said Layman, a co-author of the paper and the chief of the Section of Reproductive Endocrinology, Infertility and Genetics at GHSU.

“We usually start with a really severe phenotype. Then you start going back and looking at less severe (cases),” he said. “That kind of step could be done in the future where you look at people with milder craniofacial abnormalities. Even the intellectual disability could be very subtle. It might even be some kind of antisocial behavior or autism even, not as severe as a severe intellectual deficiency. There might be milder variants of both parts of that phenotype.”

With such a syndrome, looking at the patient’s chromosomes would tell generally where the problem is, “because the shape of the chromosome and length of the chromosome are different than normal chromosomes,” Kim said. That is like having a map of Georgia and trying to use it to find a specific car on a specific street, he said.

GHSU now has the Developmental Gene Discovery Project, in which samples taken from patients with developmental problems allow scientists to look for genes that might be the cause, Kim said.

“We are working to find the disease genes,” he said. “We are gene hunters. We want to know which gene is responsible for what kind of development in our bodies. And if it goes awry, what kind of (problem) does it cause?”

The Human Genome Project, completed nearly a decade ago, identified the 20,000 to 25,000 genes in the body.

“But that doesn’t mean we know all of the function of the genes,” Kim said. Being able to pair a gene with a specific function opens the door to the possibility of preventing or fixing the problem, he said. Likening it to an auto mechanic finding a faulty part, “then you have the possibility to replace, like a new part, (through) gene therapy or you can repair the broken part somehow.”

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Fiat_Lux
15902
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Fiat_Lux 07/05/12 - 10:02 pm
2
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The down side, of course,

is that all they can really offer at this point is the opportunity to kill a baby with flawed genes before s/he makes it out of the womb.

It's so much less inconvenient that way.

Bizkit
32894
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Bizkit 07/06/12 - 11:33 am
0
0
Since they started examining

Since they started examining genomes it has been interesting with many surprises. The dog genome is great because they suffer many diseases as humans and they often are regulated by just two genes. Most human traits have at least 3 or more genes (like eye color) and often gene networks of hundreds of genes so it can make it more difficult to find the gene or genes involved. Then there is imprinting where even a dominant gene can be turned off by methylation of cytosines or inhibtory RNAs so the phenotype doesn't match the genotype. We humans are complex creatures. Fiat the goal is genetic reprogramming where cancer genes can be turned off or repair of abnormal gene networks. Far superior to embryonic stem cells or some other strategy. Epigenetic regulation of the genome could really aid in curing diseases rather than treating symptoms. But this science is a two-edged sword with our understanding of genes in disease and behavior comes the societal and cultural issues of genetic information and the patient and responsibiities of behaviors-free will or genetic.

J3rrYcid
14
Points
J3rrYcid 11/30/12 - 03:52 am
0
0
The human body is one unique

The human body is one unique and tough specimen to study. It has thousands of genes to begin with and I reckon that it would take as much time to figure out which one serves which function. Once the miracle of such a discovery has been achieved, many amazing diagnosis could be produced and cures would follow subsequently. Not only could chronic illnesses be tackled but also ailments in different parts of the body.

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