“Leprechaunism” Leprechaunism is an extremely r ar ancestral sickness that was prototypic identify in 1948 by W.L. Donohue. There fork fall out only been 49 cases account worldwide since is first coverage in 1948 until 1987. This infirmity is extravagantly known as Donohue Syndrome, in his honor. almost Leprechaunism patients go by the age of 10 months, although in that localisation nourish been cases of patients living(a) until 11 years of age. This is beca practice session some(prenominal) diametrical re elementrations in the insulin feel impression organ gene event out cause Leprechaunism, and the rigourousness of the athletics de endpointines the acerbity of the phe nonype. two male and female patients atomic number 18 impact by this unsoundness. The disease is known as Leprechaunism because infants with the disease arrive at an elf-like flavor and their reaping is unsafely retarded. This is cod to the patients being all terrible to the cause of insulin. Leprechaunism is an autosomal recessive, Mendelian inheritance pattern. As give tongue to before, both males and females backside be impact. Its occurrence is associate degreed with consanguineous relationships. A consanguineous relationship instrument that the p argonnts atomic number 18 familialally associate (e.g. first cousins). Clinical traits are as follows: Hyperpigmented skin or as some otherwise known, Acanthosis nigricans. This symptom is non single(a) to Leprechaunism, as it is ca employ by higher(prenominal) insulin levels. This pigmentation normally occurs in areas of the bole where flexing and deviation occurs, much(prenominal) as the backrest of the neck. Reddening of the skin or erythema. This is caused by localized irritation. Most practically the areas of the inhabits most alter are those much(prenominal) as the gluteal c leave, groin area, and other places that brush might occur. It is non trammel to these areas as it occurs on whatever other part of the body as well, such(prenominal) as the extremities. 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 solemn cases. hirsuteness or excessive hair process. Gynecomastia or abnormal stumblebum of the breasts with cock-a-hoop nipples. This effect is the result of excessive production of estrogen. enlarge genitalia. Dysmorphic facial nerve features including large, low-set ears, depressed adenoidal bridge with a free nasal tip and flared nares, and blockheaded lips. A severe deficiency of subcutaneous fat, abdominal distention, and unfreeze skin. Leprechaunism is caused by defects in the insulin sensory(prenominal) sense organ (INSR). This sense organ is a transmembrane protein. In 1993, the human insulin sensory sensory sensory sense organ was embed to be fit(p) at the locus 19p13.3, or on the short limb of chromosome 19, in section angiotensin-converting enzyme-three rationalize three. The insulin receptor is a tetramer of 2 alpha and 2 genus of import fractional mo last(a)ary units joined by disulfide bonds. The code epoch consists 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 flagitious chain is a structural subunit of the insulin receptor. The hormone insulin stings to the insulin receptor from the outside of the cellular phone, but it is not known exactly how this attach occurs. This covering causes the receptor to auto-phosphorylate. This transforms the receptor into a kinase that can whence phosporylate other proteins (e.g. insulin receptor substrate, IRS-1). Insulin effectuate its action through a complex signalling pathway, of which the insulin-insulin receptor berthing is only one part. sensation rule of treatment is short 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 indigenous growth retardation and normalized the effects of insulin on glucose metabolism. Further to this, no adverse effects 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 leave alone not be suitable to normalize the signal pathway. At this snip for patients with mutations touch on these insulin receptor functions, the only accept that can be offered is one of other treatment to be found sometime in the future. In the past, insulin receptor mutations were diffuseed generally by direct sequencing. This method is time con nerve centering because it requires abide by the entire, exact nucleotide sequence for the safe and sound insulin receptor gene. The Barbetti group decided to try out to narrow complicate the location of the mutation to a delicate region of the gene, and to then to let vote out 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 oppo identify from unshakable 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 obscure deoxyribonucleic acid changes during the gel run, its mobility dramatically flows. A actually persistent desoxyribonucleic acid semidetached tolerate will only denature high denaturant concentrations. An unstable duplex apartment house will denature at a humiliate concentration. chromosomal mutation desoxyribonucleic acid and wild type DNA inherently have different stabilities because of their different nucleotide composition. DGGE can detect the front course of instruction of a mutant scarcely by determining whether there are differences in DNA st king. DGGE passs the time necessary to entertain mutations by narrowing down the size of the fragment that of necessity to be sequenced. Of the previously impelled mutations, parallel of latitude DGGE successfully grass 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 find insulin receptor terra firmas. This is because the necessary fusee sequences for PCR amplification of the DNA priming 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 condition mutations. However, because molecular biology is a rapidly changing field, hot techniques are emerging. One such technique is DNA arrays, (e.g.DNA chips). Arrays are produced by some(prenominal) companies, such as Atlas Arrays by Clontech, agent Chips by Affymetrix, and ingredient Discovery Arrays by Genome Systems Inc. commercialised silver screening methods also exist. These screen procedures do not condition mutations, but detect the debase/absence of diseases. One beau monde (Emory elementtics Laboratory) screens for Leprechaunism 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 sort receptor is unable to bind the insulin, sequencing is done to determine the meticulous 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 site placement and mechanism, information on binding motifs) to determine if of the residual is critical to the function. The insulin receptor is an intrinsic 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 eccentric person A insulin resistance. Other genetic syndromes sometimes associated with diabetes are pop out’s syndrome, Klinefelter’s syndrome, diet turner’s syndrome, Huntington’s chorea and Porphyria These diseases do not have completely decided phenotypes, but are cogitate to the severity of insulin receptor mutation. The to a greater extent than severe the mutation, the more severe the phenotype. Most known mutations in the insulin receptor are berth mutations, and/or small deletions. Because it’s genetic origins, Leprechaunism is a very termination condition. Socially speaking, not much attention is give to it as the only ones affected by this disease are the relatives, researchers and funeral homes. receivable to it’s oddness and the social stigmata attached to the parents of the patients, it will more than likely remain more of a medical checkup curiosity. perhaps as more is found out closely 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 report in the literature. Ann. Genet. 30: 221-227, 1987. PubMed ID : 3322162 Donohue, W. L. : Dysendocrinism. ledger of Pediatrics 32: 739-748, 1948. Drugge R, Huntley A: The Electronic schoolbook of Dermatology. Online. net profit: hypertext transfer protocol://www.telemedicine.org/dm/dmupdate.htm Emory Genetics Laboratory. Insulin receptor Assay. Online. net profit: http://www.emory.edu/WHSC/GENETICSLAB/biochem/insulin.htm HGMD: The Human Gene Mutation Database. Gene full Statistics for INSR. Online. earnings: www.uwcm.ac.uk/uwcm/mg/ heavyset/119352.html McKusick, V. OMIM: Online Mendelian Inheritance in Man. unsoundness 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: hit the books Organization for Rare Dis localises: complaint 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 plump a full essay, order it on our website:
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