UPDATED October 13th:
Link to background reading: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004985
This blog is devoted to BIOL 6988, a graduate level seminar in the biological sciences at Youngstown State University. While targeted towards graduate students, BIOL 6988 actively incorporates undergraduate participants in their scholastic endeavors in the biological sciences. This blog is intended as a educational tool not just for YSU students and faculty, but for anyone who wishes to contribute to an active-learning environment.
Dr. Lorimer’s lecture explored the topic of mitochondrial DNA (mtDNA) replication and human mitochondrial diseases. Human mitochondrial diseases are degenerative diseases associated with aging and an increase in mtDNA mutations. Many inherited diseases are caused by mutations in mtDNA. One in particular that is focused on in her research is MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). MELAS involves a point mutation in tRNAleu and the age of onset of the disease decreases as the generations increase. Petite mutations and biased inheritance for rho+ and rho- mtDNA were discussed. It was discovered that three sequences in WT mtDNA is necessary for hyper suppressive rho- petites in mtDNA. Dr. Lorimer then summarized standard techniques used in lab, including 2-D agarose gel electrophoresis in order to determine the why for biased inheritance. She also mentioned Clayton Model, Holt Model, Recombinant-Dependent Replication, and Rolling Circle Replication, all proposed mtDNA replication mechanisms. Future research will look at mtDNA from making single and double strands knock-out vectors.
ReplyDeleteWhat are some mitochondrial diseases and the gene(s) that are involved? Is there any current/ongoing research for the chosen disease?
I found it fascinating to learn that the onset of of MELAS occurs progressively younger with each generation. I am certainly curious as to why this occurs.
ReplyDeleteLeigh disease, also known as juvenile subacute necrotizing encephalomyelopathy, is a rare neurometabolic disorder that causes lesions in the brainstem and basal ganglia that often develop between 3 months and 2 years of age. As the disease progresses, the lesions differentiate into varying forms causing regions of demyelination, necrosis, gliosis, spongiosis, and capillary proliferation. Early signs and symptoms of the disease include lactic acidosis, dysphagia, diarrhea, vomiting. Neuromuscular function declines as the disease progresses causing dystonia, hypotonia, and ataxia. The prognosis for the disease is poor as the predicted lifespan is between 2-7 years with respiratory failure as the most frequent cause of death. While mutations to 30 nuclear genes have been identified to cause Leigh disease, 20-25% of cases are caused by a point mutation to the mitochondrial gene MT-ATP6 at nucleotide 8993, which changes a thymine to guanine. This gene codes for the ATP synthase in the oxidative phosphorylation chain, which completely inhibits the synthesis of ATP.
Mitochondrial DNA at 16,500 bases contains enough data to encode for several proteins and RNA molecules. With 37 genes, mtDNA diseases do not occur through similar mutation methods as chromosome DNA diseases. They can be inherited or can occur from spontaneous mutations. Inherited mitochondrial diseases are always inherited from the mother, not the father, because we receive mtDNA from our mother’s. However, there are genes in the normal nuclear DNA that also affect the mitochondria, so there are many diseases that involve both nuclear and mitochondrial DNA and have more balanced inheritance patterns. Mitochondrial disease affects cells differently. For this reason, the cells that need the most energy and have the most mitochondria are also the most likely to be affected by mitochondrial diseases: brain and central nervous system, heart, muscle, kidneys, and endocrine glands.
ReplyDeleteA type of mtDNA disease is Leber’s hereditary optic atrophy. This disease was first described by the German ophthalmologist Theodor Leber in 1871. Leber described four families in which a number of young men suffered abrupt loss of vision in both eyes either simultaneously or sequentially. This disease was initially thought to be X linked but was subsequently shown to be mitochondrial. LHON is a degeneration of retinal ganglion cells (RGCs) and their axons that lead to an acute or subacute loss of central vision; this affects predominantly young adult males. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria. Men cannot pass on the disease to their offspring.
I found Dr. Larimer's presentation very interesting. I never knew that some mitochondrial diseases get worse with each generation. When researching about mtDNA diseases I found a recent article that I found very interesting.( Attached link below.) Basically the researchers are looking into way to assist in the reproduction process in order to prevent the transmission of these mitochondrial DNA defects from the mother to the embryo. I found this a very interesting approach to combating the diseases. The limits to such treatments include laws and regulations against "growing babies" in a petri dish. However the advantages enable women to have a genetically related child without passing on the disease.
ReplyDeletehttp://onlinelibrary.wiley.com/store/10.1002/stem.1887/asset/stem1887.pdf;jsessionid=40568B5FA345DD91D5350D0F10CB5A50.f01t03?v=1&t=ig12cw6q&s=51243be5348f548a31f82a8c27bb89f76e3108f3
Neuropathy, ataxia, and retinitis pigmentosa (NARP) is a relatively rare disease when compared to other mitochondrial diseases. As the name implies, it is a collection of neurological conditions that have profound effects on the body. People suffering from this disease often have problems with coordination, weak muscles, numb or painful sensations in limbs, vision/hearing problems, and even heart issues. There have even been reports of age related problems including learning deficiencies for the young and dementia affecting the old. The problem is considered to be associated with mutation in the MT-AP6 gene found in mitochondrial DNA. The gene codes for a protein subunit of the ATP synthase. Without the subunit, the mitochondria generates dramatically lower amounts of ATP. However, the exact mechanism of disease is an area of ongoing research.
ReplyDeleteMitochondrial Neurogastrointestinal Encephalopathy Disease (MNGIE) is a multisystem disorder characterized by progressive gastrointestinal dysmotility, abdominal pain diarrhea, nausea, vomiting, weight loss. MNGIE disease is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. TYMP (previously known as ECGF1), the gene encoding thymidine phosphorylase, is the only gene known to be associated with MNGIE disease.TYMP mutations greatly reduce or eliminate the activity of thymidine phosphorylase. A shortage of this enzyme allows thymidine to build up to very high levels in the body. Researchers believe that an excess of this molecule is damaging to a particular kind of DNA known as mitochondrial DNA or mtDNA. A lot of the individuals with MNGIE are healthy but they have a history of presence of light fatigue. MNGIE disease is rare and it also has been confused with anorexia nervosa and other classes of GI diseases.
ReplyDeleteSome of the treatment strategies include attention to swallowing difficulties and airway protection; antibiotics for intestinal bacterial overgrowth; morphine; and physical and occupational therapy
http://www.ncbi.nlm.nih.gov/books/NBK1179/
Myoclonic Epilepsy with Ragged Red Fibers (MERRF) is a mitochondrial disease that affects muscles and nervous system. The symptoms of this disorder emerge during childhood. MERRF is a rare condition which affects 1 in 5000 worldwide. The most common cause for MERRF is mutations in the MT – TK genes. Sometimes mutations in the MT-TL1, MT-TH, and MT-TS1 genes may cause symptoms of MERRF
ReplyDeleteThe mutations that cause MERRF harm the ability of mitochondria in order to produce energy make proteins and use oxygen.
Here is a research that gives more info about MERRF
http://www.ncbi.nlm.nih.gov/books/NBK1520/
Mitochondria, is the organelles that generate energy for the cell. They convert the energy of food molecules into the ATP that powers most cell functions and are thefore found in every cell of the human body except red blood cells. Most of mitochondrial diseases are caused by caused by mutations in the mitochondrial DNA or mutations in genes of the nuclear DNA, whose gene products are translocated into the mitochondria as mitochondrial proteins. The diseases may also be acquired mitochondrial conditions.
ReplyDeleteThe subclass of these diseases that produces neuromuscular symptoms are mostly referred to as a mitochondrial myopathy. For MT-TL1, MT-TK, and MT-TE genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. mutatation in this genes can cause mitochondrial diabetes and deafness. People with this condition have diabetes and sometimes hearing loss, particularly of high tones.
Other mitochondrial genetical conditions include Leigh syndrome, hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodesneuropathy, ataxia, and retinitis pigmentosa, and progressive external ophthalmoplegia.
Pyruvate dehydrogenase complex deficiency (PDCD) is an inherited inborn error of metabolism meaning those afflicted can’t convert some of the food they eat into energy. This is due to fewer pyruvate dehydrogenase complex that help break down carbohydrates and sugars into energy and cells cease to maintain their proper function. Children with PDCD can experience poor muscle tone, neurological damage (brain cell injury, cognitive delays, and seizures), poor food intake, and lethargy. Also the inability to properly break down carbohydrates causes accumulation of lactic acid that can exacerbate symptoms and produce new ones like low blood pressure, vomiting, high heart rate, and rapid breathing. One PHDA1 gene responsible for creating the pyruvate dehydrogenase enzyme is found on the X chromosome. Boys seem to be more affected than girls since they have one X chromosome and one Y chromosome, while girls have two X chromosomes and are able to produce more of the enzyme than boys. Other genes associated with PDCD are not on the X chromosome and affect boys and girls equally. Most of the changes in PHDA1 occur spontaneously. Neither parent is a carrier so the chance of having another affected child is low, but it has been seen that families with a PHDA1-mutated child have higher chances of having another affected child. When the problem lies in other genes besides PDHA1, it is possible for both parents to carry the gene change and pass it on. Sodium dicholoroacetate (DCA) helps to activate the enzyme complex and decreases the lactic acidosis in individuals with enzyme deficiency but that drug is still undergoing investigational studies.
ReplyDeletehttp://www.umdf.org/site/c.8qKOJ0MvF7LUG/b.8852461/k.B677/PDCD.htm
Alpers' disease is a progressive, neurodevelopmental, mitochondrial DNA depletion syndrome characterized by three co-occurring clinical symptoms: psychomotor regression (dementia); seizures; and liver disease. It is an autosomal recessive disease caused by mutation in the gene for the mitochondrial DNA polymerase POLG. The disease occurs in about one in 100,000 persons. Most individuals with Alpers' disease do not show symptoms at birth and develop normally for weeks to years before the onset of symptoms. Diagnosis is established by testing for the POLG gene. Symptoms typically occur months before tissue samples show the mitochondrial DNA depletion, so that these depletion studies cannot be used for early diagnosis. About 80 percent of individuals with Alpers' disease develop symptoms in the first two years of life, and 20 percent develop symptoms between ages 2 and 25.
ReplyDeleteThe NINDS is currently supporting gene linked neurodegenarative diseases such as Alpers. Goals are to increase understanding of the diseases to prevent and cure them.
http://www.ninds.nih.gov/disorders/alpersdisease/alpersdisease.htm
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes affects many of the body's systems, particularly the brain, nervous system, and muscles. Signs and symptoms appear during childhood followed by a period of normal development. Most individuals experience stroke-like episodes beginning before age 40. Repeats of this can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function. The stroke-like episodes can be mis-diagnosed as epilepsy by a doctor not aware of the MELAS condition. Most people with MELAS have lactic acidosis. Less common, people may experience involuntary muscle spasms, impaired muscle coordination, hearing loss, heart and kidney problems, diabetes, epilepsy, and hormonal imbalances. The genes affected by MALAS (MT-ND1, MT-ND5) encode proteins that are part of NADH dehydrogenase. The other genes (MT-TH, MT-TL1, and MT-TV) encode mitochondrial specific tRNAs. Mutations in MT-TL1 cause more than 80 percent of all cases of MELAS. This mutation impairs the ability of mitochondria to make proteins, use oxygen, and produce energy. There is no known treatment for the disease, which is progressive and fatal. However there have been some supplements that have shown promise and given hope to MELAS patients.
ReplyDeleteAs a sign of gratitude for how my son was saved from Alpers' Disease , i decided to reach out to those still suffering from this.
ReplyDeleteMy son was diagnosed of Alpers' Disease in 2013 and it was really tough and heartbreaking for me because he was my all and the symptoms were terrible, he always have seizure , and he always complain of loss of cognitive ability . we tried various therapies prescribed by our neurologist but none could cure him. I searched for a cure and i saw a testimony by someone who was cured and so many other with similar body problem, and he left the contact of the doctor who had the cure to Alpers' Disease . I never imagined Alpers' Disease has a natural cure not until i contacted him and he assured me my son will be fine. I got the herbal medication he recommended and my son used it and in one months he was fully okay even up till this moment he is so full of life. Alpers' Disease has a cure and it is a herbal cure contact the doctor for more info on drwilliams098675@gmail.com on how to get the medication. Thanks admin for such an informative blog.