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Solving A Medical Mystery: Cause Of Rare Type Of Dwarfism Discovered

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For children born with Saul-Wilson syndrome, and their parents, much of their lives are spent searching for answers. First defined in 1990, only 14 cases are known worldwide. And the cause of the syndrome — characterized by short stature, microcephaly (small head), hearing loss and early developmental delays — remained unknown. Today, these individuals have answers.

“This is the news I have been waiting for my whole life,” says Monica Zaring, who has Saul-Wilson syndrome.

“A diagnosis with Saul-Wilson syndrome is just that — a name. I feel so grateful for all the doctors who never gave up, even when they didn’t have answers, and I hope this information will help more people in the future.”

Scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP), in collaboration with researchers and clinicians at the National Human Genome Research Institute (NHGRI), the University of Edinburgh, the University of Oregon, and the Nemours/Alfred I. duPont Hospital for Children, have uncovered the cause of Saul-Wilson syndrome: an alteration in the gene that codes for a protein that is part of a component that controls and maintains the cell’s protein packager, the Golgi complex (pronounced gol-je). The study published today in the American Journal of Human Genetics.

“Children with Saul-Wilson syndrome and their parents live with many unanswered questions,” says Carlos R. Ferreira, M.D., medical geneticist at the NHGRI.

“Knowing the underlying cause of the condition is a major step forward for these indviduals and could help scientists find a treatment for the syndrome. This finding also advances our understanding of the genome and Golgi complex’s impact on human health, which may help us understand more skeletal disorders.”

Proteins, the workhorses of our body, are transported inside of our cells via packages called vesicles. These packages travel from one cellular organ, the endoplasmic reticulum (ER), to the Golgi complex, which resembles a stack of pancakes. Keeping the Golgi in working order relies on a protein complex called COG, which has eight subunits.

“The Golgi complex is where proteins ‘get ready for the dance,'” says co-first author Zhijie Xia, Ph.D., postdoctoral researcher in the laboratory of Hudson Freeze, Ph.D., co-senior author of the paper and director and professor of the Human Genetics Program at SBP.

“Here, proteins are modified in a variety of ways — such as sugars being added or removed — which affects their ultimate function in the body.”

Using the latest genetic technology, the scientists analyzed 14 people with Saul-Wilson syndrome. All the individuals had the very same change in just one copy of the gene that codes for COG4 protein, which is part of the Golgi complex. This change in the COG4 gene arose spontaneously (de novo), meaning each parent did not have the mutation. As a result, one amino acid, the building block of proteins, was swapped for another. Specifically, glycine was replaced by arginine.

Further study revealed that in the cells of people with Saul-Wilson syndrome, packages of proteins moved slowly from the ER to the Golgi complex, but then rapidly returned — similar to a delivery truck that drives slowly to your home but speeds back to the warehouse. The size of the Golgi complex was halved. The scientists also found the Golgi complex’s ability to add sugars to one protein, decorin, was altered. This protein travels out of the cell and helps support the collagen in skin.

“With the advent of genetic sequencing, we are learning of more conditions that are caused by de novo changes, including autism and epilepsy. Additionally, we are finding more disorders that are caused by heterozygous mutations — which are found only on one gene, versus both genes,” says Freeze.

“Studying cases of heterozygous, de novo mutations could provide insights into additional mysterious conditions. Our lab is already undertaking a more comprehensive study to understand the impact of the COG4 mutation on protein production and stability.”

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Paternal Transmission Of Epigenetic Memory Via Sperm

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Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across generations, however, remains mysterious.

Susan Strome’s lab at UC Santa Cruz has been making steady progress in unraveling the mechanisms behind this phenomenon, using a tiny roundworm called Caenorhabditis elegans to show how marks on chromosomes that affect gene expression, called “epigenetic” marks, can be transmitted from parents to offspring. Her team’s most recent paper, published October 17 in Nature Communications, focuses on transmission of epigenetic marks by C. elegans sperm.

In addition to documenting the transmission of epigenetic memory by sperm, the new study shows that the epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in the offspring (germ cells give rise to eggs and sperm).

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome, a distinguished professor of molecular, cell, and developmental biology.

Epigenetic changes do not alter the DNA sequences of genes, but instead involve chemical modifications to either the DNA itself or the histone proteins with which DNA is packaged in the chromosomes. These modifications influence gene expression, turning genes on or off in different cells and at different stages of development. The idea that epigenetic modifications can cause changes in gene expression that are transmitted from one generation to the next, known as “transgenerational epigenetic inheritance,” is now the focus of intense scientific investigation.

For many years, it was thought that sperm do not retain any histone packaging and therefore could not transmit histone-based epigenetic information to offspring. Recent studies, however, have shown that about 10 percent of histone packaging is retained in both human and mouse sperm.

“Furthermore, where the chromosomes retain histone packaging of DNA is in developmentally important regions, so those findings raised awareness of the possibility that sperm may transmit important epigenetic information to embryos,” Strome said.

When her lab looked at C. elegans sperm, they found the sperm genome fully retains histone packaging. Other researchers had found the same is true for another commonly studied organism, the zebrafish.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” Strome said.

Her lab focused on a particular epigenetic mark (designated H3K27me3) that has been well established as a mark of repressed gene expression in a wide range of organisms. The researchers found that removing this mark from sperm chromosomes causes the majority of the offspring to be sterile. Having established that the mark is important, they wanted to see if it is sufficient to guide normal germline development.

The researchers addressed this by analyzing a mutant worm in which the chromosomes from sperm and egg are separated in the first cell division after fertilization, so that one cell of the embryo inherits only sperm chromosomes and the other cell inherits only egg chromosomes (normally, each cell of an embryo inherits chromosomes from both egg and sperm). This unusual chromosome segregation pattern allowed the researchers to generate worms whose germ line inherited only sperm chromosomes and therefore only sperm epigenetic marks. Those worms turned out to be fertile and to have normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

While the study shows that epigenetic information transmitted by sperm is important for normal development, it does not directly address how the life experience of a father can affect the health of his descendants. Strome’s lab is investigating this question with experiments in which worms are treated with alcohol or starved before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said.

“Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

By demonstrating the importance of epigenetic information carried by sperm, the current study establishes that if the environment experienced by the father changes the epigenetics of sperm chromosomes, it could affect the offspring.

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Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren

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A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in mice publishing on October 16 in the open-access journal PLOS Biology by Pradeep Bhide of Florida State University in Tallahassee and colleagues. The effect, which was not caused by direct secondhand exposure, may be due to epigenetic changes in key genes in the father’s sperm.

Exposure of mothers to nicotine and other components of cigarette smoke is recognized as a significant risk factor for behavioral disorders, including attention deficit hyperactivity disorder, (or ADHD) in multiple generations of descendants. Whether the same applies to fathers has been less clear, in part because in human studies it has been difficult to separate genetic factors (such as a genetic predisposition to ADHD) from environmental factors, such as direct exposure to cigarette smoke.

To overcome this difficulty, Deirdre McCarthy, Pradeep Bhide and colleagues exposed male mice to low-dose nicotine in their drinking water during the stage of life in which the mice produce sperm. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.

Nicotine and cigarette smoke have been previously shown to cause widespread epigenetic changes, Bhide said.

“The fact that men smoke more than women makes the effects in males especially important from a public health perspective. Our findings underscore the need for more research on the effects of smoking by the father, rather than just the mother, on the health of their children.”

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Nutrition Has A Greater Impact On Bone Strength Than Exercise

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ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a bigger positive impact on bone strength. University of Michigan researchers looked at mineral supplementation and exercise in mice, and found surprising results–nutrition has a greater impact on bone mass and strength than exercise. Further, even after the exercise training stopped, the mice retained bone strength gains as long as they ate a mineral-supplemented diet.

“The longer-term mineral-supplemented diet leads to not only increases in bone mass and strength, but the ability to maintain those increases even after detraining,” said David Kohn, a U-M professor in the schools of dentistry and engineering.

“This was done in mice, but if you think about the progression to humans, diet is easier for someone to carry on as they get older and stop exercising, rather than the continuation of exercise itself.”

The second important finding is that the diet alone has beneficial effects on bone, even without exercising. This surprised Kohn, who expected exercise with a normal diet to fuel greater gains in bone strength, but that wasn’t the case.

“The data suggests the long-term consumption of the mineral-supplemented diet could be beneficial in preventing the loss of bone and strength with age, even if you don’t do exercise training,” he said.

Combining the two amplifies the effect.

Most other studies look at effects of increasing dietary calcium, Kohn said. The U-M study increased calcium and phosphorous, and found benefits to increasing both.

This isn’t to suggest that people run out and buy calcium and phosphorus supplements, Kohn said. The findings don’t translate directly from mice to humans, but they do give researchers a conceptual place to start.

It’s known that humans achieve peak bone mass in their early 20s, and after that it declines. The question becomes how to maximize the amount of bone when young, so that when declines do begin, people start from a better position, Kohn said.

In addition to testing bone mass and strength, Kohn and colleagues performed a full battery of mechanical assessments on the bone, which is important because the amount of bone doesn’t always scale with or predict the mechanical quality of the tissue.

They tested the mice after eight weeks of training and supplemented diet or normal diet, and then after eight weeks of detraining.

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