Professor URLs, Jan 26th

Genetic discovery about childhood blindness paves way for new treatments
Posted: 12 Jan 2015 03:13 PM PST
Finding genes for retinal degenerations has immediate benefits for people living with blindness and vision loss, their families, and their physicians. Establishing a genetic cause confirms the clinical diagnosis at the molecular level, helps predict the future visual prognosis, suggests therapies, and allows some patients to join clinical trials. While more than 200 genes for retinal degenerations have been identified, approximately 40-50 percent of cases remain a mystery.

Robert Koenekoop's clinic at the Montreal Children's Hospital of the McGill University Health Centre (MUHC) with blindness and dwarfism due to Oliver McFarlane Syndrome (OMS), her unknown mutation sparked an international gene hunt. "It was like finding a needle in a haystack," said Dr. Koenekoop, who is also a researcher at the Research Institute of the MUHC and a Professor of Human Genetics, Paediatric Surgery and Ophthalmology at McGill University. "It was so obvious to all of us that this was big; a new gene, a possible new disease pathway, a new treatment avenue." Although we've known about the PNLPA6 gene for more than 45 years, no one had identified that mutations in this gene can lead to retinal degeneration -- until now. Phospholipids are located in our cell membranes where they influence the membrane's shape and functioning. They also influence how cells communicate with each other by determining the signals that are able to pass through cell membranes. When phospholipids stop doing what they are supposed to do, important signals get lost and cells can no longer maintain their structures or respond to their environment.

These potentially game-changing results were published on January 9, 2015:. Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nature Communications, 2015; 6: 5614 DOI: 10.1038/ncomms6614.

Insights into a rare genetic disease
Posted: 19 Jan 2015 12:43 PM PST
People with the NGLY1 mutation have many severe symptoms, from delayed development and epilepsy to abnormal liver function and the inability to make tears. In a big step towards understanding the effects of a rare genetic disease, research by scientists implicates the enzyme ENGase as the factor responsible for deficient protein degradation that occurs in the absence of mouse Ngly1 gene expression. Recently, a grassroots effort initiated by families and clinicians led to the discovery of a human genetic disorder with severe consequences that is linked to a mutation in the human NGLY1 gene. First creating a model glycoprotein for examining this process in animal cells. Next, they expressed the model protein in cells derived from four types of mice -- wild-type, Ngly1 knockout, Engase knockout, and double knockout -- and measured how much of the model protein was degraded and how much of the undegraded portion still had attached sugar chains. First, removal of sugar chains by ENGase appeared to have created a form of the protein that, in the absence of Ngly1 could not be degraded properly. Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ERAD in Ngly1-defective cells. Proc. Natl. Acad. Sci., January 2015 DOI: 10.1073/pnas.1414593112

Genetics underpinning antimalarial drug resistance revealed
Posted: 19 Jan 2015 09:45 AM PST
Researchers have identified a series of mutations that could help to improve early detection of resistance to our most effective antimalarial drug. The largest genome-wide association study to date of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin. The results could help to improve early detection of emerging artemisinin resistance. The largest genome-wide association study to date of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin. The results could help to improve early detection of emerging artemisinin resistance. Whilst artemisinin resistant parasites do appear to have migrated across national borders, this only happened on a limited scale and, in fact, the most widespread kelch13 mutation, C580Y, appeared to have emerged independently on several occasions. Notably parasites along the Thailand-Myanmar border appear to have acquired this mutation separately from those in Cambodia and Vietnam. Crucially, parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nature Genetics, 2015; DOI: 10.1038/ng.3189