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Archive - Sep 26, 2013


New Dwarfism Mutation Identified in Dogs; Also Candidate for Human Dwarfism

Professor Hannes Lohi’s research group at the University of Helsinki and Folkhälsan Research Center in Finland has identified a mutation in the ITGA10 gene that causes chondrodysplasia (dwarfism) in two dog breeds, the Norwegian Elkhound and the Karelian Bear Dog. The research revealed a new chondrodysplasia gene in dogs, and a candidate gene for human chondrodysplasias. The finding has implications on bone biology as well as canine health. A genetic test can now be used to identify mutation carriers in the two affected dog breeds. The study was published online in the open-access journal PLOS ONE on 25 September 2013. The ITGA10 mutation causes autosomal recessive disproportionate short-stature dwarfism of varying severity. The appearance of affected dogs is characterized by considerably shorter limbs than normal dogs, and other skeletal abnormalities may follow, including bowed forearms, abnormal digits, and malformed femoral heads. The ITGA10 gene codes for an integrin subunit that assembles into a cartilage-specific collagen receptor, found in the growth plates of long bones. The receptor is important for the process of endochondral ossification, in which the cartilage cells first proliferate, and are then replaced by bone tissue. Accordingly, several abnormalities have been found in the growth plates of affected dogs both in radiographic and histological examinations. The causative mutation was mapped to a specific region on canine chromosome 17 by comparing the genomes of affected and healthy dogs. Further analysis of this chromosomal region revealed a single nucleotide change in the ITGA10 gene, which disrupts the gene by introducing a signal that prematurely ends the production of the encoded integrin subunit.

Genetics and Diet Interact to Form Microbiome

A Mayo Clinic researcher, along with collaborators, has shown that an individual's genomic makeup and diet interact to determine which microbes exist and how they act in the host intestine. The study was modeled in germ-free knockout mice to mimic a genetic condition that affects 1 in 5 humans and increases the risk for digestive diseases. The findings were published online on September 23, 2013 in the PNAS. "Our data show that factors in the differences in a host's genetic makeup — in this case genes that affect carbohydrates in the gut — interact with the type of food eaten. That combination determines the composition and function of resident microbes," says Purna Kashyap, M.B.B.S., a Mayo Clinic gastroenterologist and first author of the study. He is also a collaborator in the Microbiome Program of the Mayo Clinic Center for Individualized Medicine. Roughly 20 percent of humans lack the gene that encodes proteins for processing a specific carbohydrate, a sugar in the intestinal mucus called fucose. The interaction shown by the research team is valuable because many bacteria are adept at utilizing carbohydrates such as fucose, which are abundant in the gut. Confronted with diets that have little or no complex plant sugars, these bacteria are forced to change their function, especially in hosts that lack fucose. This was seen with the altered metabolic gene expression of one of the key microbes in the gut — Bacteroides thetaiotaomicron. Changes in microbial membership or function as demonstrated in this study may, in turn, foster a "digestive landscape" that can promote inflammatory conditions such as Crohn's disease. The microbiome represents millions of microbes in the gut and elsewhere in the body. They perform specialized functions to help keep metabolism in balance.

“Zone in with Zon”—Exosomes: Tiny Packets of RNAs with Major Significance and Potential

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, dated September 23, 2013, focuses on a discussion of “exosomes,” tiny ~30-100 nm extracellular vesicles discovered 30 years ago. These exosomes are released from cells and can fuse with the membrane of target cells and enable the transmission of exosome informational cargo, e.g., protein and RNA, into the target cell. According to Dr. Zon, “the ability to influence gene expression in distant cells through exosomes presents a remarkable model for cell-to-cell signaling that offers an entirely new perspective on intercellular communication. This also has potential therapeutic applications, such as in diagnosis, intervention, and artificial gene/mRNA delivery.” Dr. Zon cites an explosion of exosome-focused peer-reviewed articles in the last ten years, as evidence of increasing awareness of the importance of these information-loaded vesicles. He also highlighted a 2007 article by Valadi et al. that reported that exosomes from mast cells contained mRNA from ~1,300 genes, many of which were not present in the cytoplasm of the donor cell. He noted that in vitro translation showed that the exosome mRNA was functional and analysis of total RNA from the exosomes revealed the presence of small RNAs, including miRNAs. In addition, the RNA from mast cell exosomes was transferrable to other mast cells. Dr. Zon said this publication has been cited more that 1,300 times, particularly in the molecular biology of cancer. Dr. Zon goes on to discuss recent work documenting the release of exosomes by the human placenta into maternal circulation throughout pregnancy, as well as the role of tumor-released exosomes in promoting cancer developmement. Dr.