i need help with these questions:
1) which organelle is affected in this disease condition?
2) describe the structure of the organelle.
3) describe the role of this organelle in a healthy individual.
4) how is the organelle formed?
so, does anyone know the answer to these questions? this sounds like a "i'm a student and this is my home work question. "
Good luck! Nerve cells are the one's damaged. You can find the answers to the other 3 questions at the wikipedia article: .http://en.wikipedia.org/wiki/Nerve_cell) Abstract
Tay-Sachs is an autosomal recessive disease produced by mutations in both alleles of a gene (HEXA) on chromosome 15. HEXA codes for the alpha subunit of the enzyme 尾-hexosaminidase A, an enzyme originated in lysosomes; these are organelles that rupture big molecules for recycling by the cell. Usually, 尾-hexosaminidase A aids to breakdown a lipid called GM2 ganglioside, but with Tay-Sachs individuals, the enzyme is not present or only in very small amounts permitting unnecessary buildup of the GM2 ganglioside in neurons (Genes, 2005). The goal here is to create a model for Tay-Sachs disease. This will be done by looking into three research teams that are trying to produce the Tay-Sachs model. The first is producing mice defiant in hexosaminidase A through disruption of the Hexa gene by homologous recombination (Yamanaka, 1994), another is using diagnostic single strand conformational polymorphism (SSCP), (Ainsworth, 1990), and the last team is performing splice junction mutation in Ashkenazi Jews with Tay-Sachs disease (Myerowitz, 1998).
Introduction
There are many diseases in the world that have no cure. One of those diseases is Tay- Sachs disease. There is no treatment for Tay-Sachs excluding for temporary helpful care. Eventually, almost all of the children that are afflicted die by the age of four (Family, 2004). Tay Sachs disease is named for Warren Tay (1843-1927), a British ophthalmologist who in 1881 first described the 鈥渃herry-red鈥?spot on the retina of the eye (a classic characteristic of the disorder) and for Bernard Sachs (1858-1944), a New York neurologist, who described the cellular metamorphosis of Tay-Sachs and realized an enlarged occurrence in the Eastern European Jewish population of 1887 (Health, 2002). There are clear genetic patterns to the development of Tay-Sachs. This disease is a fatal genetic disorder that harms large amounts of a fatty substance called ganglioside GM2 which build up in the nerve cells in the brain. Infants with Tay-Sachs disease seem to develop like normal babies for the first few months of life. However, as nerve cells become inflated with this fatty material, persistent decline of mental and physical abilities are produced (Genes, 2005). Definite chemical chaperones have been used for numerous lysosomal storage diseases, such as Fabry disease, Gaucher disease, GM1 gangliosidosis, and adult Tay-Sachs and Sandhoff disease (Bonapace, 2004). The baby becomes deaf, blind, and loses the ability to swallow. Muscles start to weaken and paralysis begins. A rarer type of this disease occurs in patients well in their twenties to early thirties and is characterized by instability of gait and growing neurological decline. The degree of appearance and the age at onset of Tay-Sachs can vary from juvenile and adolescent forms that show paralysis, dementia, blindness and early death to a chronic adult form that demonstrate neuron dysfunction and psychosis (Genes, 2005). The standard juvenile kind of Tay-Sachs is the most common. There are other uncommon deficiencies of the hexosaminidase A enzyme that occasionally are incorporated under the name of Tay-Sachs disease. These regularly are referred to as juvenile, chronic, and adult-onset forms of hexosaminidase A deficiency. Pretentious persons have reduced amounts of the hexosaminidase A enzyme that is absent completely in the classical. This might explain why symptoms start later in life and, usually are calmer than the classical Tay-Sachs disease. Children with juvenile hexosaminidase A deficiency increase symptoms between the ages of 2 and 5 that look like those of the classical form. Even though the path of the disease is slower, death usually occurs by age 15. Symptoms of chronic hexosaminidase A deficiency can also begin by age 5; however they are less mild than those from the infantile and juvenile forms. Mental abilities, vision, and hearing stay whole; but there can be slurred speech, muscle weakness, muscle cramps, tremors, unsteady gait, and mental illness. People with adult-onset hexosaminidase A shortage show many of the same symptoms as patients with the chronic form, except the symptoms begin later in life (Medical, 2005). Patients with Tay-Sachs have a "cherry-red" mark in the rear of their eyes. This circumstance is caused by inadequate action of an enzyme called hexosaminidase A, which catalyzes the biodegradation of acidic fatty resources known as gangliosides. These are made and biodegraded quickly in life as the brain matures. Patients and carriers of Tay-Sachs disease can be recognized by a general blood test which measures hexosaminidase A activity. Mutual parents must be carriers in order to have a child with the disease. When both parents are known to carry a genetic mutation in hexosaminidase A, there is a 25% chance with each pregnancy that the baby will have Tay-Sachs disease. Prenatal testing of pregnancies is available if desired (NINDS, 2005). Tay-Sachs is a genetic metabolic disease regularly connected with Ashkenazi Jews, has also been found in the French Canadians of Southeastern Quebec, the Cajuns of Southwest Louisiana, and other populations all over the world (Genes, 2005). Even though Tay-Sachs disease can happen in families of different ethnic backgrounds, it is significantly more prevalent among Ashkenazi Jews. It is expected that roughly 1 in 25 Ashkenazi Jews are carriers of Tay-Sachs disease. This means that 1 in 900 Jewish couples might possibly have a child afflicted with the disease. The remaining population as an incidence of only 1 in 300 people to have the Tay-Sachs gene (Family, 2004). The frequency for a couple, which are not Ashkenazi Jews, to get together is 1 in 90,000. Currently there is no treatment available for Tay-Sachs disease. The importance has been put on public education, carrier screening, and prenatal diagnosis for the prevention of this devastating disease. Right now Tay-Sachs testing research has found roughly 40,000 carriers. Almost 1,100 carrier couples have been identified and counseled about their 25% chance of having an affected child. Prenatal analysis for this disease is obtainable and very consistent. Prenatal diagnosis is achievable by administering tests like chrionic villous sampling or amniocentesis. Currently, over 2,500 pregnancies have been examined (Diseases, 2005). This type of genetic testing should be done before conception. The testing can be done after, however, at a risk to the embryo. Testing over the past 25 years has decreased the occurrence of Tay-Sachs by 90% (Family, 2004). There has beenan examination into nonsense-mediated mRNA decay (NMD) of a mutant HEXA communication in lymphoblasts resultingfrom a Tay-Sachs disease patient homozygous for the normal frameshiftmutation. Mutant mRNA was nearly undetectable inthe cells and amplified to about 40% of typical in theexistence of the translation inhibitor cycloheximide. Then the stabilizedtranscript was established in the cytoplasm in connection with polysomes (Rajavel, 2001). There is currently no successful therapy for Tay-Sachs or other lysosomal storage disorders that involve the central nervous system. The goal here is to create a model for Tay-Sachs disease. This will be done by looking into three research teams that have are trying to produce the Tay-Sachs model. The first is producing mice totally defiant in hexosaminidase A through disruption of the Hexa gene by homologous recombination (Yamanaka, 1994), another is using diagnostic single strand conformational polymorphism (SSCP), (Ainsworth, 1990), and the last team is performing splice junction mutation in Ashkenazi Jews with Tay-Sachs disease (Myerowitz, 1998).
Results & Discussion
Yamanaka and associates believe that researching the 尾-hexosaminidase A deficient mice ought to be helpful for creating strategies to initiate resourceful enzyme and genes into the CNS. This model could be important for researching the biochemical and pathologic transform happening throughout the course of the disease (1994). Although several mutations havebeen acknowledged as the cause of TSD, the most frequent is a 4-bpinsertion in exon 11 (1278ins4) of the 14-exon HEXA gene, reduction causesthe reading frame by 100 codons. Patient fibroblasts homozygousfor this type of frameshift mutation have untraceable levels of the nonsense-containingmRNA, although transcription is done normally. It isnot the frameshift itself, but the untimely termination in codon9 nucleotides located later on the DNA chain that is the foundation of the low-mRNA phenotype(Rajavel, 2001). There are two types of hexosaminidase, A (acid) and B (basic), they are isozymes that are divisible by ion-exchange chromatography in mice and humans. However, just 尾-hexosaminidase A can successfully hydrolyze the sulfated substrate MU-GlcNAc-6-SO4, since it has the 伪 subunit. A liver homogenate from Hexa +/+, normal, mice following chromatography on a Mono Q column, established two fractions of 尾-hexosaminidase movement (Figure 1). The non-supported fraction corresponded to 尾-hexosaminidase B, and hydrolyzed the neutral substrate MU-GlcNAc, however not the sulfated substrate MU-GlcNAc-6-SO4. The supported fraction communicated to 尾-hexosaminidase A and hydrolyzed both the sulfated and neutral substrates. Liver extracts from Hexa -/-, mice with Tay-Sachs, exhibited plenty of 尾-hexosaminidase B with <1% of normal 尾-hexosaminidase A activity. The enzyme summary from Hexa +/-, carrier mice, showed transitional levels of 尾-hexosaminidase A relative to 尾-hexosaminidase B (Yamanaka, 1994). Figure 1. Hexa -/- mice are completely lacking in 尾-hexosaminidase A activity. Liver samples from Hexa
+/-, +/-, and -/- mice were tested by ion-exchange chromatography on a Mono Q column. The fractions
gathered were assayed for 尾-hexosaminidase action by sampling them every hour with MU-GlcNAc-6-SO4 or MU-GlcNAc. The dotted line shows the NaCl concentration gradient (Yamanaka, 1994).
About 79% of Ashkenazi Jews who are carriers contain an addition of 4 nucleotides (GACT) in Hexa exon 11 (Sanchez, 2004) Then Yamanaka and associates tested the mice to see if there was an irregular neurological manifestation were found (Table 1) between the three types of mice (1994). Another team studying Tay-Sachs was looking into a simplified non-radioisotopic method of B1 variant. A recently created method for the exposure of single base mutations (PCR-SSCP) has modified to a rapid non-radioisotopic method and practical way to the diagnosis of a B1 variant of Tay-Sachs disease. They realized and reported a B1 variant genotype that had two different point mutations in exon 6 of the alpha subunit gene (G574C; G598A) (Ainsworth, 1990). Verification of the mutations was prepared on DNA augmented from genomic material collected from the proband. This mutant allele is of maternal origin, not paternal. Fibroblast-derived genomic DNA were applied as a template for symmetric PCR intensification of a 135 bp DNA segment surrounding the region had both mutations (Ainsworth, 1990). The plasmid (Figure 2) was used to establish the contents of only the 135bp DNA segment which has both point mutations established that this slow moving band signify the single mutant sense strand of DNA
Figure 2. PCR products (20 碌l) were produced by an asymmetric amplification (40 cycles). This was run
about 5 hours at first at 50 V, 3 hours, then at 100 V reached a temperature of 30掳C. The gel was then
silver stained (Bio0Rad). Lane 1: control, normal DNA, Lanes 2 and 6: paternally resultant DNA, Lanes 3
and 7: maternally resultant DNA, Lanes 4 and 8: DNA resultant from the proband, and Lane 5: DNA
resultant from a plasmid has the mutant 135 bp DNA segment (Ainsworth, 1990).
There is confirmation against a single defect within the ethnic group in some Ashkenazi Jews that have been diagnosed with Tay-Sachs. This was accomplished by splicing the junction mutation (Myerowitz, 1998). This also introduces innovations in thermal cycling that uncouple primer annealing from probe detection and reduce the constraints on the design of allele-discriminating probes (Sanchez, 2004). The current research isolated the alpha-chain gene from an Ashkenazi Jewish patient, GM2968, with classic Tay-Sachs disease and evaluated its nucleotide sequences with that of a healthy alpha-chain gene in the promoter region, exon and splice junction regions, and polyadenylylation signal area. A single difference was noticed between the sequences: at the 5' boundary of intron 12, a guanosine in the preserved splice junction dinucleotide sequence G-T had been changed to a cytidine. The modification is assumed to be practical and important to the effect in aberrant mRNA splicing (Myerowitz, 1998). The research is mandatory for separation of the mutant 伪-chain gene known to have the mutation. The DNA (GM2968) is acquired from the fibroblasts of an Ashkenazi Jewish patient with classic Tay-Sachs (Myerowitz, 1998). The assay for the splicing junction mutation is used for classification of the modification in the patient and heterozygote carriers. The splice junction mutation is supported on the observation that transform it from a guanosine into a cytidine (Figure 3) at the 5鈥?edge of intron 12 created a new Dde 1 constraint site in the mutant DNA segment (Myerowitz, 1998). Figure 3, shows the nucleotide sequence breakdown of the 伪-chain genes from a normal subject and from
an Ashkenazi Jewish patent that has the classic form of Tay-Sachs which has GM2968 as templates for the
sequence reaction. The transformation from a guanosine into a cytidine at the 5鈥?edge of intron 12 in
GM2968 is shown by the arrow (Myerowitz, 1998).
Conclusion Even though it has been shown that degradation of cytoplasmic nonsense HEXA mRNA, it is still possible to exclude the idea that some TSD transcriptsare tarnished. (Rajavel, 2001). Management of the late onset type of Tay-Sachs with a gangliosidosis synthesis inhibitor indicates research is moving the right direction. Future studies are looking into researching different ideas about Tay-Sachs the disease can be better understood. Some of those ways is by being able to produce mice totally defiant in hexosaminidase A through disruption of the Hexa gene by homologous recombination (Yamanaka, 1994), another is to use diagnostic single strand conformational polymorphism (SSCP), (Ainsworth, 1990), and a final way is to perform splice junction mutation in Ashkenazi Jews with Tay-Sachs disease (Myerowitz, 1998). The effectiveness of these types of research needs to be clearer and more effective before science can learn the proper way to fight Tay-Sachs disease. The efficiency and other healing methods on patients with the infantile type of the disease are very restricted since the degree of neurological damage before birth is unknown. The intricacy in reversing this damage will make it difficult to create a successful method for the infantile form of the disease. There is belief that the late onset forms of Tay-Sachs may prove reactive to treatment, and this treatment along with the DNA and enzymatic testing programs presently in use will progress to the eventual control of this disease (Gene, 2005).
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