Findings on Genetic Basis of Development and Disease

09/09/2010: Researchers at Johns Hopkins identified two gene mutations that enable some ovarian cancers, ARID1A and PPP2R1A. ARID1A appears to be a classic tumor suppression gene, in the same class as BRCA1 and BRCA2. The mutations cause gene transcription errors, thus depriving the body of a natural tumor suppression mechanism. This gene has also been implicated in some breast and lung cancers.

09/15/2010: Scattered reports from various countries report patients returning from medical procedures in India have brought a superbug with them. Here superbug means bacterium that has acquired a gene called NDM1 (New Delhi metallo-beta-lactamase 1). The superbug was first reported in Britain in 2007 in the Lancet Medical Journal. NDM1 manufactures an enzyme that deactivates current antibiotics. NDM1 can easily attach itself to common bacteria types; so far it is associated mostly with bacteria that are found in the gut and urinary tract. One death is linked to the NDM1 to date.

09/16/2010: The rate of progression of Alzheimer’s Disease has been linked to a mutation (SNP rs1868402) in a gene coding for tau protein. The resulting phosphorylated tau (ptau181) has been observed to accelerate the progression of AD by up to a factor of six, but is not linked to age of onset. ‘Hyperphosphorylation of tau influences the microtubule network, impairs axonal transport, and leads to formation of neurofibrillary tangles — and eventually cell death’.

09/19/2010: The FDA’s antiquated insistence on years-long full controlled trials before drug approval is more and more implicated in inhumane outcomes for individuals who end up dead because of a random assignment to a ‘placebo’ group. The purpose of controlled trials is to measure long term relative effectiveness of competing therapeutics in extending life. As Collins emphasized in his book, the FDA needs to become more progressive in its authorization process. The Seattle Times reported on a trial of a new drug PLX4032 for treating metastatic melanoma in a class of patients with a specific genetic mutation (B-RAF) of the tumor cells; annually, 68,000 patients are diagnosed with melanoma and half of these have cells with the B-RAF allele. Clinical trials had shown tumor growth was halted for 8 months in 81% of trial patients (compared to a 2 month slow down in 15% of patients for the ‘placebo’ drug). The FDA has an accelerated approval process for highly promising drugs, but still requires a parallel controlled trial. Yet the drug company did not request accelerated approval for a drug this effective, because once it was available in even limited quantity, no one could be induced to join a controlled trial and risk a 50-50 chance of not being assigned the drug. Thus the trial would need to be concluded before making the drug available. Market competition demanded that full drug approval be obtained as quickly as possible. The ethical dilemma at the core of such issues needs to be resolved, but there is still vigorous debate on the issue among oncologists. Perhaps classes of drugs designed to exploit specific genetic characteristics should be fully approved based solely on high effectiveness during clinical trials on advanced end-of-life stage patients. In the story, two cousins became eligible for trials. The first had very advanced cancer and qualified for a clinical trial in which he received PLX4032. The second was then diagnosed, but had to wait for the controlled trial and then was unfortunate to be assigned the placebo. The first is still alive and just attended the second cousin’s funeral.

09/27/2010: A mutation has been noted that prevents gene KCNK18 from switching on and producing the protein TRESK. The mutation interferes with the TRESK potassium channel involved in nerve sensitivity regulation in the brain. People with the mutation seem more susceptible to a type of migraine that is preceded by a sensual aura. Perhaps a synthetic TRESK pill would be therapeutic for patients with disrupted TRESK production. No mention is seen in the article summary of a connection to people that suffer painless migraines (i.e. just the aura, such as visual flashing jagged colored lines, but no subsequent headache).

11/03/2010: Mutations to the gene CNTNAP2 (contactin-associated protein-like 2) have been linked to autism and language disorders. Brain imaging shows that persons with certain gene variants have an excess of neuronal connections in the frontal lobe, and a sparseness of connections in other places.

11/04/2010: SNPs responsible for changing five amino acids in the HLA-B protein have been linked with improved ability to control HIV. HLA-B protein is important for helping the immune system tag and destroy cells infected by a virus.

03/01/2011: Mutations in insulin receptor gene HMGA1 are associated with up to 10% of type 2 diabetes cases. Four functional variants of HMGA1 turned up as linked to type 2 diabetes, in order of commonality:

  • IVS5-13insC, up to 15.77 times more common in the diabetes patients than controls P<0.001).
  • c.310G>T (p.E104X) variant found in 14 patients and no controls (Bonferroni-adjusted P=0.01)
  • c.*82G>A variant (rs2780219) found in 46 patients and five controls (Bonferroni-adjusted P<0.001)
  • c.*369del variant found in 24 patients and no controls (Bonferroni-adjusted P<0.001)

Any of these mutations causes failure to produce insulin receptor protein.

08/09/11: The number of gene mutations linked to MS has risen to 57. 80% of the mutated genes are known to have immune system functionality.

MS is not directly inherited. There is no smoking gun gene, but rather a wide variety of common mutations that in combination with each other and environmental factors lead to the disease, primarily in people of northern European roots. MS is largely unknown in equatorial indigenous peoples.

Earlier studies have led to a hypothesis that Vitamin D deficiency enables an abnormal response by the body to the Epstein-Barr virus in some people, triggering MS onset. Scotland has the highest percentage of MS cases by population.

08/09/11: A gene therapy experiment has proven successful in attacking CLL tumors, the most common type of leukemia. T-cells are extracted and modified, then re-infused. These modified cells attack and destroy tumor cells. The experiment is ready for broader public trials.

The targeted CD-19 molecule in tumor cells also occurs in some normal cells tied to the immune response, so immune system booster drugs must also be given.  Some modified T-cells persist in the body and some transform into memory T-cells. This may be useful for keeping the disease suppressed, but may have other long term effects that need to be studied. While the toxic effects to normal tissue can be controlled in CLL therapy, similar approaches to other tumor types may need to address long-term toxicity.

08/22/2011: Mutations in a single gene known as UBQLN2 cause hereditary forms of Lou Gehrig’s Disease, ALS and ALS with dementia, likely through defective degradation of abnormal protein clumps, according to a research letter published online in Nature. Even patients without the UBQLN2 mutation had features of the disrupted pathway, suggesting that it is a “common pathological feature in a wide spectrum of ALS and ALS/dementia,” according to Dr. Teepu Siddique of Northwestern University in Chicago and coauthors.

ALS is usually sporadic, meaning of unknown origin. But up to 10 percent of cases run in familes. Several mutations have been identified, accounting for roughly 30 percent of hereditary ALS. But the cause of the remaining cases remain unknown, the authors wrote.

The UBQLN2 mutation, which results in a defective protein called ubiquilin2, was discovered in a five-generation family affected by ALS. Initially, investigators identified 206 genes of interest, 41 of which were considered relevant to the disease. “The exact function of ubiquilin 2 is not well understood,” the authors noted. “However, there is increasing evidence that ubiquilins, together with their interactions with other proteins, may be involved in neurodegenerative disorders.”

Siddique and colleagues searched for additional UBQLN2 mutations in 188 members of other families with a history of ALS or ALS with dementia. The work led to identification of four additional mutations, none of which was present in a mutation database or in 928 control samples.

The researchers then examined tissue from ALS patients for the presence of ubiquilin 2 in clumps of protein building up inside dying neurons, a hallmark of ALS. They found ubiquilin2 in those clumps in both brain and spinal-cord tissue. To determine whether ubiquilin2 is involved in other forms of ALS, the authors examined autopsy specimens from 47 patients, including those with sporadic and familial forms of the disease. They found ubiquilin2-positive clumps in all ALS cases, indicating that it is a common component of protein aggregates of a wide variety of ALS.

The normal protein ubiquitin is found in all eukaryotic cells, where it is used to tag damaged protein for destruction as part of the cellular protein turnover process. The 2004 Nobel Prize in chemistry was awarded for providing this foundational understanding.

“These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well,” the authors stated. “Further elucidation of these processes may be central to the understanding of pathogenic pathways, which then should provide novel molecular targets for the design of rational therapies for these disorders.”

05/19/2016: Nature Communications: Gene associations identified for human facial development.

Genes were identified that regulate the growth of bone and cartilage, and the shape of the face. GLI3, which drives cartilage growth, had the strongest effect on the breadth of the nostrils. DCHS2 was linked to nose pointiness. The bone-growth gene RUNX2 modified nose bridge width. PAX1 is a key developmental transcription factor which has been shown to affect chondrocyte differentiation through its participation in a regulatory pathway that also includes RUNX2. A missense mutation of PAX1 is known to cause various skeletal and facial abnormalities. Related PAX3 is shown to influence nasion position. A fifth gene, EDAR, was found to influence mandible length.

5/23/1026: American Journal of Human Genetics: Loss of Y chromosome (LOY) in blood cells of aging men is implicated in increased risk for cancer, Alzheimers, and shorter life span, according to a study at Uppsala University.

A study of 3200 European men showed that 17% experienced loss of Y chromosome in some blood cells, and that loss increased with age. Those with greatest percent of cell LOY experienced a 7-fold higher risk for Alzheimers. This, coupled with earlier research regarding LOY and cancer, is suggestive that some genes on the Y chromosome may have importance to immune system function.


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