Population Isolates and Ophthalmic Diseases.

This article is discussing the relevance between genetic isolates and ophthalmic diseases. It will mainly focus on population isolates and the role they play in searching for the underlying genes responsible for monogenic and complex heterogeneous eye diseases. For some background information, population isolates are a group of individuals who are known to have descended from the founder of a population. Because of this, they have been able to maintain a relative degree of genetic homogeneity due to geographical and cultural isolation. There have been many gains in better understanding the genetic etiology (the genes responsible for casing disease) of age-related macular degeneration and eye diseases that are similar. However, the etiology of the heritable blinding diseases (e.g. primary open-angle glaucoma and myopia) are still issues at hand that are working with the population isolated theory, to hopefully gain a better understanding. Population isolates are found in both recessive traits and complex traits

Population isolates are effective ways to further investigate recessive traits. A high frequency rate of new mutations occurring within humans makes it conceivable that there is a high prevalence of recessive diseases in some isolated populations. This happens because of random chance; also known as genetic drift. This also explains why some alleles are able to be more common or rare over consecutive generations. An increased risk of recessive diseases is also associated with consanguineous relationships meaning blood relatives (incest). Consanguinity is lower than it was in isolated populations and this has been shown in a Finnish isolate study. In the study there were thirty monogenic (meaning only one gene) recessive disorders that are more frequent there than anywhere else. One account for this may be linked to non-random migration of families clustering in small geographical areas.

Retinoschisis is an X-linked retinal disease related to population isolates. This is described as the worsening visual cavity, radial and peripheral superficial retinal detachment. Cases with highest prevalence were reported in Finland based upon age and sex (88 males) from 31 families. This particular ophthalmic disease is located on the short arm of the X-chromosome leaving insight into three other founder mutations with high prevalence disease in Finland families. Some other noted examples of retinal diseases within consanguineous relationships is complex strabismus and nanophthalmos. Complex strabismus is a misalignment of the eye and varies with gaze direction. Several Saudi Arabian families were studied and reported to have a basis for autosomal recessive complex strabismus. Nanophthalmos is very rare and is described by small axial lengths with high-hypermetropia on three separate loci of the eleventh chromosome. There are two forms of this that exist, autosomal dominant and recessive, and there is evidence of a founder effect in the Faroe Islands.

Population isolates are also effective means for studying complex traits in ophthalmic diseases. Age Related Macular Degeneration (AMD) is one example of many complex traits. AMD is characterized by two forms, wet and dry. Dry makes up on average 80% of AMD with being described as serous detachment of the retinal pigment epithelium (RPE). AMD varies considerably between ethnic groups. There was a link reported between the US and Japanese populations in correlation with the complement factor H gene contributing to nearly half of all cases of AMD.

Another example of complex traits is primary open angle glaucoma which is asymptomatic with gradual progressive loss of peripheral vision. This is also accompanied by having a cupped head of the optic nerve. This particular complex trait is reportedly found in the French-Canadian populations of Quebec. Four families were studied and later concluded to have been carrying four MYOC mutations that were believed to have been derived from the original Quebec settlers. Also, 14 additional families with glaucoma carried eight of the MYOC mutation from these original settlers.

In conclusion, it has been both successful and helpful in using population isolates. We now have a better knowledge of recessive traits as well as complex traits and the role they play in ophthalmic disease. Isolated populations may only allow for the identification for a few major diseases; however these genes are identified more efficiently than those from non isolated populations. Being able to identify founder effects helps simplify the analysis of genetic diseases as well as helps the screening service in any populations.

Marcee Amos

Giving HIV a Poor Reception: New AIDS Treatment Tinkers with Immune Cell Genes

An article written by Bob Roehr titled, “Giving HIV a Poor Reception: New AIDS Treatment Tinkers with Immune Cell Genes” shows hope for a possible cure for the HIV virus in the future. HIV has long been perceived as an incurable disease that has killed millions of people throughout the course of history. However, scientists have started to learn how HIV enters the body and from that they are now trying to block the entry site to prevent HIV from taking over.

HIV enters cells in the body by attaching to a special region on a cell called a receptor molecule; in this case the receptor is called CD4. Then the virus attaches itself to a co-receptor molecule called CCR5. Scientists then discovered a mutation to the gene that encodes for CCR5. A mutation is a permanent change in the sequence of DNA in a gene. The mutation (called delta-32) prevents CCR5 from being created. With this said, if an individual inherits only one copy of this gene then they have a less likely chance of contracting HIV and if they do, the disease will play out much slower since they will have fewer CCR5 receptors for the virus to attach to. An individual who inherits the mutant gene from both parents will not have any CCR5 receptors which make it close to impossible for HIV to enter the cell.

When all of this was realized, pharmaceutical companies sought out a way to chemically block the CCR5 receptor thus artificially blocking HIV from entering the cell. With this new insight came the production of a small molecule drug called maraviroc.

I chose this article because before I read this article I only thought that HIV entered the body based on what my teachers told me in health class. Their explanation was that it is spread and enters the body through bodily fluids. I never thought about it past that point at a cellular and molecular level. This article enlightened me and has helped me understand how it enters the body on those levels and I found it extremely fascinating. The thought about a potential cure for the HIV virus will be one of the biggest breakthroughs in medical and genetic history.

Ross Beckner

Pittsburgh researchers single out genes for major depression

I chose to blog about a major problem in today's world known as depression. I found an article that studies the genes and the interactions that may cause depression. Scientists at the University of Pittsburgh wanted to find certain genes that would increase a person's chances of developing depression. The study was done with 81 families that had known depressive disorders. The scientists are trying to gain as much knowledge on depression as possible because it is a very serious disorder. Depression affects 10% of the population, and with more knowledge comes more effective treatments and drugs. Previous studies have shown that between 40% and 70% of depression risks are due to genetics. There have always been issues with discovering the actual genes because they believe that many genes are involved. These scientists believe that the difficulty is due to the fact that many genes may cause depression, and it actually depends on the combination of the genes and the individual that leads to the development of depression. They feel they need to perform this study because people with depression are found to live a shorter lifespan. The study itself found that there are small regions on chromosomes where these genes reside. This is what seems to bring on the actual depressive behaviors. Genetics also has a lot to do with depression in gender. It is believed that due to the differences in gender, depression is more likely in women than in men. There is a gene known as CREB1 that has to do with the regulatory protein known as CREB. This protein is known to have a lot to do with different factors in the body and is thought to be the cause of many depressive disorders, as well as other psychiatric disorders. They have identified 18 new genetic regions that may have a great deal to do with CREB and the influence it has on depression. They believe that identification of susceptibility genes could greatly help the early diagnosis and treatment of depression. This could really help the human lifespan. I have learned a lot from this article. I knew that depression was genetic, but I was not aware that the cause is due to more than one gene. I was interested in this article for personal reasons. I know what it is like to have depression and not understand the direct cause. I did not know about the protein CREB or the gene CREB1. It was very interesting to learn about the genetic regions and how much of the population is actually affected by depression. Magen Deane

RNA Interference used to inhibit Huntington's disease translation

RNA interference is used to prevent the expression of specific genes; hopefully, targeting unique rather than simply abundant sequences. The author’s objective in this article was to use RNA interference to suppress the CAG repeats in the Huntington’s gene that lead to the disease state. This research was initially discouraged as the siRNAs used to originally target genes showed little to no discrimination, as several genes were silenced instead of just the target. However; recent advances have allowed peptide nucleic acid antisense reagents to work with a much higher degree of selectivity than prior studies. The study compares the inhibition of the Huntington’s disease allele with the inhibition of the normal allele and other mRNA’s containing both CAG and CUG repeats.
This study showed that selectivity was not only great in the repeat targeting duplex but that this selectivity could even be further enhanced by specific mutations in which the binding efficiency was reduced. Further it was observed that different RNA duplexes silence gene production in different ways. Duplex 7, which had full complementarity to the mutant allele responsible for Huntington’s disease proved to be the most effective. The RNAi actually decreases the rate of transcription which decreases the prevalence of the mutant phenotype. Lastly the most interesting discovery was that an up-regulation of the wild type Huntington allele resulted when inhibition of the mutant occurred via duplex. This could be a result of the action of the RNAi itself, but most likely is a compensatory mechanism for the inhibition of one of the alleles. Basically in the heterozygote cases when a mutant allele is repressed or inhibited the wild type allele is transcribed, or translated, or both more frequently in order to compensate for the protein shortage. This provides some hope for, not just Huntington’s disease but treatment for any disease caused by an expansion of a repeated three gene sequence in the near future. In conclusion the recent advances in the field have taken a technique that was previously disregarded as too hazardous to a patient’s health and begun to evolve into a specific and targeted technique with the promise of one day treating a series of genetic disorders.
I chose this article because I plan to have a future in drug research and it proposed a treatment for a genetic disease. The entire article was interesting as I did not have much in the way of prior knowledge of RNA interference at all. Further I find it somewhat incredible that RNA, the component use for translation, can also be an inhibitor of the very action the text book teaches as almost its’ sole purpose. Lastly it was interesting to see that even at the DNA level the human body does attempt to compensate whenever it is obstructed, especially in this case. Shutting down or restricting mutant alleles will actually cause the other allele to become more pronounced has huge implications if it applies to more than just this set of genes.

J Harper.

Hereditary Hemorrhagic Telangiectasia

HHT is a genetic disorder that causes abnormalities of blood vessels. Most of the blood vessels in the body of a person with HHT are normal. However, some of the vessels do have an abnormality. There are two types of blood vessels: arteries and veins. An artery does not usually connect directly a vein. Usually there are very small blood vessels called capillaries that connect artery to a vein. A person with HHT has a tendency to form blood vessels that lack the capillaries between an artery and vein. This means that arterial blood under high pressure flows directly into a vein without first having to squeeze through the very small capillaries. This place where an artery is connected directly to a vein tends to be a fragile site that can rupture and result in bleeding. When a blood vessel is abnormal this way, it is called telangiectasia. Telangiectases tend to occur at the surface of the body such as the skin and the mucous membrane that lines the nose. The telangiectases of HHT occur primarily in the nose, skin of the face, hands, and mouth and the lining of the stomach and intestines, lungs, liver and brain. We are still not sure why these abnormalities occur in these specific areas.

The study I picked had to deal with mutations of HHT found in Spanish families. They identified two different mutations, 22 ALK1 mutations and 15 ENG mutations, in independent Spanish families affiliated with HHT. They identified mutations in 37 unrelated families. An analysis of all the symptoms were recorded for each patient that was analyzed. They found there were more abnormalities in HHT1 patients than HHT2 patients. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG.

Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1) in the Spanish population. This data goes along with another previous study that was based on Mediterranean countries such as France and Italy, but different to Northern Europe or North America. There was a significant increase of abnormal blood vessels associated with HHT1 over HHT2 in these families.

Christina Moreno

MicroRNAs involved in transformation of liver cancer stem cells

The existence of cancer stem cells in hepatocellular carcinoma (also known as HCC), which is a cancer of the liver, has been confirmed. This discovery was made possible by characterizing certain cells based on the information gathered from the Hoechst 33342 dye used to stain stem cells. This stain is easy to use on stem cells since it is easily “excited” by ultraviolet light. Recent discoveries in microRNA biology have revealed that these types of RNA's do indeed play an important role in the development of embryos and the formation of tumors. This type of RNA protein is“noncoding”and made up of 19 to 25 nucleotides in length. They regulate gene expression by inhibiting and transforming the layers of mRNAs through base-pairing. However, it is still unclear which microRNAs actually take part in the conversion of normal cells into tumor cells during the production of cancer in the liver.

Cancer stem cells have been identified in cells located in the blood and in solid tumors, including hepatocellular carcinoma (HCC). The isolation and characterization of cancer stem cells are usually based on the presence of stem cell markers. Although, in many tissues, certain markers of bodily stem cells are still unclear. There have been many attempts made to identify cancer stem cells in tumors, based on the results from the use of the Hoechst 33342 dye. The ability to isolate these cells by sorting them, makes it possible to improve both normal bodily stem cells and cancer stem cells without the use of stem cell markers.

Researchers used a gene knockout mouse model to show that microRNAs may be critical regulators of the development of organs in embryonic stem cells. However, data suggests that “dysregulation” of these microRNAs occurs in a many types of cancers, such as lung, colon, and liver. The effects of these specific RNAs in both cancer production and the differences of normal stem cells suggest that microRNA may be involved in the transformation of normal stem cells into cancer stem cells.

Hepatocellular carcinoma is one of the most malignant tumors in existence. However, when researchers divide certain population cells, the presence of liver cancer stem cells in many hepatocellular carcinomas cell lines can be verified using this technique. However, few experiments have focused on the characterization of population cells isolated from HCC cells. The researchers in this study saw that if normal stem cells and liver cancer stem cells could be enriched when the side population cells were isolated, then they could create an in vitro model to determine whether this type of liver cancer could develop through these types of bodily cells.