Posts Tagged ‘cmg’

Clues from the resilient

Wednesday, July 5th, 2017

Clues from the resilient Potential 2nd site mutations that neutralize #Mendelian-disease mutations

“For 127 catastrophic Mendelian diseases (those caused by a single gene such as cystic fibrosis and ataxia-telangiectasia), there are presently 164 genes harboring 685 known recurrent variants that are highly penetrant and causal for deleterious traits, most typically manifesting in individuals before the age of 18 (). …For common diseases, the observed small effect sizes of individual gene variants limit diagnostic potential, and given that most variants identified have an unclear function, how to target the corresponding gene for therapeutic intervention is typically unclear. For rarer Mendelian disorders, although genetics directly implicate a specific gene in a disease, a majority of such cases relate to loss-of-function mutations. Designing small molecules to fix the corresponding broken protein has proven difficult….
The prominent role of second-site mutations and environmental factors that enable resistance to (or buffer against) disease traits has been well established in a multitude of model organisms from yeast to mice (–). Screening for second-site mutations in “resilient” individuals that prevent disease-causing alleles from manifesting their effects could identify targets to which drugs would be designed to disrupt their function, as opposed to targeting the disease-causing gene directly. Genetic studies examining seemingly healthy people have revealed, for example, rare mutations in chemokine (C-C motif) receptor type 5 (the co-receptor for human immunodeficiency virus) that block HIV infection (), and secondary mutations in fetal globin genes that modify the severity of sickle cell disease by buffering primary mutations in β-globin genes ()

Lanosterol reverses protein aggregation in cataracts : Nature : Nature Publishing Group

Monday, August 17th, 2015

Lanosterol reverses protein aggregation in cataracts A finding from rare-disease #exome sequencing cc @solvemendelian

…Lanosterol is an
amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygousLSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSSprevents intracellular protein aggregation of various
cataract-causing mutant crystallins.

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Tuesday, July 29th, 2014

Lots of LOF! — Boenke mentions: LOF mutations in SLC30A8 protect against T2D Power of combining data for mult. variants #GSPfuture

Singled out for sequencing : Nature Methods : Nature Publishing Group

Monday, January 27th, 2014

Nice piece on #SingleCell Seq w/ implications for #cancer, neurosci, &c. Singled out for #sequencing HT @naivelocus

Lots on brain, cancer & prenatal sequencing, viz:

For example, as part of the Single Cell Analysis Program supported by the US National Institutes of Health Common Fund, Kun Zhang’s team will generate full transcriptomes from 10,000 cells in three areas of the human cortex. They will group the transcripts into cell
types—perhaps redefining those cell types in the process—and map the transcripts back to cortical slices of the brain. Single-cell RNA-seq itself is no longer a barrier. “If you have a good cell, and you want to get a measure of the transcriptome, there is more than one option that can lead you to that goal,” Zhang says. In general, however, extracting the neurons posthumously, minimizing RNA degradation and preserving some of the neuronal spatial information is challenging, and the group is evaluating several approaches, Zhang says.

Europe Pumps $50M into Genome-based International Rare Disease Projects

Monday, March 11th, 2013