“Leprechaunism” Leprechaunism is an extremely r ar ancestral sickness that was showtime identify in 1948 by W.L. Donohue. There fork turn out only been 49 cases reported worldwide since is first describe in 1948 until 1987. This malady is also known as Donohue Syndrome, in his honor. almost Leprechaunism patients go by the age of 10 months, although in that location nourish been cases of patients living(a) until 11 years of age. This is beca practice school term some(prenominal) diametrical mutations in the insulin spirit organ gene hug out cause Leprechaunism, and the clumsiness of the mutation determines the acerbity of the phe nonype. some(prenominal) male and female patients are impact by this disease. The disease is known as Leprechaunism because infants with the disease hand over an elf-like flavor and their reaping is unsafely retarded. This is referable to the patients being all in all disgusting to the cause of insulin. Leprec haunism is an autosomal recessive, Mendelian inheritance pattern. As stated before, both males and females can be change. Its occurrence is associated with consanguineous relationships. A consanguineous relationship room that the parents are ge gainically associate (e.g. first cousins). Clinical traits are as follows: Hyperpigmented skin or as some other known, Acanthosis nigricans. This symptom is non exclusive to Leprechaunism, as it is ca apply by in high spirits insulin levels. This pigmentation normally occurs in areas of the system where flexing and deviation occurs, much(prenominal) as the plunk for of the neck. Reddening of the skin or erythema. This is caused by localized irritation. Most oftentimes the areas of the body most affected are those much(prenominal) as the gluteal cleft, groin area, and other places that friction might occur. It is not exceptional to these areas as it occurs on any other part of the body as well, such(prenominal) as the ex tremities. Pincer nails. This is where the ! nails of the feet and hands have an increased inner folding. This often gives the visual effect of claws in severe cases. hirsuteness or undue hair reaping. Gynecomastia or abnormal stumblebum of the breasts with prominent nipples. This effect is the result of excessive production of estrogen. enlarge genitalia. Dysmorphic facial features including large, low-set ears, depressed emaciated bridge with a broad nasal tip and flared nares, and fat lips. A severe lack of subcutaneous fat, abdominal distention, and faint skin. Leprechaunism is caused by defects in the insulin sensory sense organ (INSR). This sense organ is a transmembrane protein. In 1993, the human insulin sensory sensory sense organ was launch to be located at the locus 19p13.3, or on the short arm of chromosome 19, in section ace-three seamster three. The insulin receptor is a tetramer of 2 alpha and 2 genus of import subunits joined by disulfide bonds. The coding chronological succession consis ts of 22 exons, with 11 exons coding for the alpha subunit and 11 coding for the beta subunit. It is postulated that the class I MHC heavy chain is a geomorphologic subunit of the insulin receptor. The hormone insulin stings to the insulin receptor from the outside of the cell, but it is not known exactly how this stick occurs. This maskinging causes the receptor to auto-phosphorylate. This transforms the receptor into a kinase that can accordingly phosporylate other proteins (e.g. insulin receptor substrate, IRS-1). Insulin cause its action through a complex signalling pathway, of which the insulin-insulin receptor mystifying is only one part. One determine of treatment is shortly being investigated. This consists of long term treatment (years) of the patients with recombinant human insulin-like growth factor-I (IGF-I). In a least one Leprechaunism patient, injections of IGF-I prevented the post endemical growth retardation and normalized the effects of insulin o n glucose metabolism. Further to this, no adverse eff! ects were noticed. Depending on the specific nature of a patients mutation, the effectiveness of IGF-I treatment varies. For example, if the mutation affects the phosphorylation business leader of the insulin receptor, or its fount on cell surfaces, the IGF-I injections will not be suitable to normalize the signaling pathway. At this snip for patients with mutations impact these insulin receptor functions, the only hope that can be offered is one of other treatment to be found sometime in the future. In the past, insulin receptor mutations were diffuseed mostly by direct sequencing. This method is time consuming because it requires determining the entire, exact nucleotide sequence for the safe and sound insulin receptor gene. The Barbetti group decided to reach to narrow complicate the location of the mutation to a half-size region of the gene, and to then to begin sequencing. They proposed to narrow down the mutation search by performing DGGE (Denaturing Gradient Gel Electrophoresis) on fragments of the insulin receptor gene. DGGE is variant from regular gelatine electrophoresis because a denaturation gradient is construct into the gel. Both jibe and perpendicular DGGE were used to analyze segments of the insulin receptor gene isolated from the patients. When double desolate deoxyribonucleic acid alters during the gel run, its mobility dramatically flows. A very abiding DNA semidetached house will only denature high denaturant concentrations. An unstable duplex house will denature at a lower concentration. chromosomal mutation DNA and wild type DNA inherently have different stabilities because of their different nucleotide composition. DGGE can detect the front margin of a mutant simply by determining whether in that respect are differences in DNA st efficiency. DGGE reducings the time necessary to think mutations by narrowing down the size of the fragment that necessarily to be sequenced. Of the previously deter mined mutations, pair DGGE successfully shop 12 of! 16 mutations. Perpendicular DGGE detected the 4 mutations that parallel DGGE didnt. The success rate in mutation detection was vitamin C% by these means. DGGE is ideal for diagnostic work in dislodge insulin receptor terra firmas. This is because the necessary fusee sequences for PCR amplification of the DNA primer have already been designed and published. Â Â Â Â Â Â Â Â The purpose for using DGGE was to decrease the time necessary to characterize mutations. However, because molecular biology is a rapidly changing field, new techniques are emerging. One such technique is DNA arrays, (e.g.DNA chips). Arrays are produced by several companies, such as Atlas Arrays by Clontech, agent Chips by Affymetrix, and broker Discovery Arrays by Genome Systems Inc. Commercial screening methods also exist. These screen procedures do not characterize mutations, but detect the overbear/absence of diseases. One company (Emory Genetics Laboratory) screens for Leprec haunism by evaluating the ability of the insulin receptor to bind insulin in fibroblasts. The insulin is iodine-labeled and is compared to cell lines defined as positive and negative controls.
If the test receptor is unable to bind the insulin, sequencing is done to determine the precise mutation. Because of its nature, DGGE cannot detect the difference in the midst of polymorphisms and mutants. The significance of mutations is left up to the researcher. The researcher must use other sources of selective information (i.e. active post placement and mechanism, information on binding motifs) to determine if of the sleep is critical to the function. The insulin rec! eptor is an integral part of the insulin signaling pathway. In fact, most tidy sum with defective insulin receptors are completely insensitive to the effects of insulin and are severely diabetic. Mutations in the insulin receptor can cause several diseases, such as Leprechaunism, Rabson-Mendenhall syndrome and guinea pig A insulin resistance. Other genetic syndromes sometimes associated with diabetes are stilt’s syndrome, Klinefelter’s syndrome, food turner’s syndrome, Huntington’s chorea and Porphyria These diseases do not have completely decided phenotypes, but are related to the severity of insulin receptor mutation. The much than than severe the mutation, the more severe the phenotype. Most known mutations in the insulin receptor are nonsense mutations, and/or small deletions. Because it’s genetic origins, Leprechaunism is a very termination condition. Socially speaking, not much attention is paid to it as the only ones affected by this d isease are the relatives, researchers and funeral homes. receivable to it’s tolerateder and the social stigmata attached to the parents of the patients, it will more than likely remain more of a medical curiosity. perhaps as more is found out about this disease, applications can be found for it’s successful treatment. Bibliography Barbetti R, Pablo GV, Gejman SI, Taylor NR, Aleessandro C, Bonora E, Pizzo P, Moghetti P, Muggeo M, Roth J: Detections of Mutations in Insulin sense organ Gene by Denaturing Gradient Gel Electrophoresis. Diabetes 41: 411-15, 1992. Bajaj et al. Biochim Biophys Acta 916:220-26, 1987 Cantani, A.; Ziruolo, M. G.; Tacconi, M. L. : A rare polydysmorphic syndrome: Leprechaunism--review of forty-nine cases reported in the literature. Ann. Genet. 30: 221-227, 1987. PubMed ID : 3322162 Donohue, W. L. : Dysendocrinism. journal of Pediatrics 32: 739-748, 1948. Drugge R, Huntley A: The Electronic schoolbook of Dermatology. Online. net profi t: hypertext transfer protocol://www.telemedicine.org! /dm/dmupdate.htm Emory Genetics Laboratory. Insulin sense organ Assay. Online. lucre: http://www.emory.edu/WHSC/GENETICSLAB/biochem/insulin.htm HGMD: The Human Gene Mutation Database. Gene broad Statistics for INSR. Online. Internet: www.uwcm.ac.uk/uwcm/mg/summary/119352.html McKusick, V. OMIM: Online Mendelian Inheritance in Man. Disease Entry: #246200 Leprechaunism. Online. Internet: www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?246200 Nakae J, Kato M, Murashita M, Shinohara N, Tajima T, Fujieda K. J Clin Endocrinogic Metabolism 1998 Feb;83(2):542-9 NORD: reflect Organization for Rare Disorders: Disease Information: Leprechaunism. Online. Internet: http://206.105.18.10/nord/rdb_sum/387.htm OMIM: Online Mendelian Inheritance in Man. Disease Entry: I147670 Insulin Receptor; INSR. Online. Internet: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?147670#TEXT www.vghtpe.gov.tw/~meta/dmclass.htm If you want to get a full essay, order i t on our website:
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