Rare Genetic Problem: Oculocutaneous Albinism - Essay Example

?QS1. OCULOCUTANEOUS ALBINISM http asia.ensembl.org/Homo_sapiens/Transcript/Exons?db=core;g=ENSG00000077498;r=11:88910620-89028927;t=ENST00000263321 Oculocutaneous albinism is a rare genetic problem. It is an autosomal recessive disorder. 1 in 20,000 people are born with this disorder. The condition affects Oculocutaneous albinism is categorized into 4 different types (Types I, Type II, Type III and Type IV) and affects people from different ethnic groups as well as from different geographical regions. Types I and II are most common. Americans and African Americans suffer mostly from Type II, while Type III is prevalent among South Africans and Type IV is primarily found among Japanese and Koreans. 4 different genes are responsible for OCA- TYR, OCA2, TYRP1 and SLC45A2.One of the most commonly found mutation is in gene TYR which causes type I OCA. TYR is better known as tyrosinase gene. A normal TYR gene codes for the enzyme Tyrosinase. Mammalian melanogenesis is regulated at more than 90 loci in the gene. Tyrosinase is expressed the melanocytes and is a type I melanosomal glycoprotein. They play a pivotal role in melanin production in the melanocytes. Tyrosinase is produced in the ribosome and is transported through the endoplasmic Reticulum and Golgi apparatus into the melanocytes. Soon after this transportation melanin biosynthesis is initiated. Melanin is the pigment responsible for coloration of hair, skin and parts of the eyes (iris and retina). The enzyme converts protein tyrosine into another compound known as L-hydroxy-phenylalanine (DOPA) which is again converted to form DOPAquinone (dihydroxy phenylalanine quinine). This conversion is a critical step in melanin production process. This conversion is followed by a series of chemical reactions till melanin pigment is formed which imparts the color. TYR is present on 11q14-q21 and contains about 5 exons. The 5 exons span more than 65kb on chromosome 11q.Genetic testing has determined that TYR gene mutations mostly occur in the coding region and not in the proximal promoter region of the gene. More than 100 mutations have been identified to occur in the gene. The nature of the mutation are deletion, polymorphism, nonsense, frame shift and splice-site mutations. Sometime mutation in the gene eliminates tyrosine activity altogether giving rise to OCA type IA while other mutations causes’ diminished TYR activity leading to slight coloration which is known as OCA type IB. Patients with OCA IA perfectly white hair, pale skin and lightly colored eyes and they do not tan. Patients with OCA IB have white hair, pale skin and eyes but the color of hair and eye may darken with age and the skin is slightly prone to tan. OCA Type II can be further categorized for milder forms of the disease. Symptoms of Oculocutaneous albinism include hypopigmentation of skin and hair, congenital nystagmus, reduction in pigment in the iris and iris translucency, vision acuity reduction, impairment of color vision, photophobia etc. Deficiency of pigment in the iris diminishes proper functioning and reflects light leading to refractive errors. Patients with this disorder are prone to skin cancer. Molecular sequence analysis of the TYR coding gene is done to facilitate implementation of management strategies because clinical manifestations of the different types of albinism overlap each other. However, owing to presence of a pseudogene of TYR which has similar exons similar to exons 4 and 5 of Tyr gene, analysis of mutation is hampered. There is no cure for this disorder. The diagnosis includes better management or the disorder and alleviation of further problems or complications. Managing the disorder includes protection against exposure to light by using covering clothes, hats, sunscreens and sun shades since even the slightest exposure to sun rays may cause skin burns. Other steps include usage of spectacles to correct eye problems and frequent testing for skin cancer. In case the patient develops nystagmus, eye surgery is often recommended to rectify the abnormality in the movement of the eyes. It is recommended that couples with heterozygous gene (carriers) must take genetic counseling in order to determine the chances of inheritance of the disorder in their offsprings. Being an autosomal disorder most carriers do not realize that they are carrying a mutated gene for albinism since carriers do not show any signs or symptoms of the disease. (Picture Courtesy: http://www.ojrd.com/content/2/1/43/figure/F3) (Picture courtesy: http://albinismdb.med.umn.edu/oca1map.htm_) References Albinism database. http://albinismdb.med.umn.edu/oca1mut.html. Mutations of the tyrosinase gene Associated with OCA1 Genetics Home Reference. http://ghr.nlm.nih.gov/gene/TYR . TYR Genetics Home Reference. http://ghr.nlm.nih.gov/condition/oculocutaneous-albinism. Oculocutaneous Albinism Genetic Testing registry. http://www.ncbi.nlm.nih.gov/gtr/tests/18502/.Test for Oculocutaneous Albinism Type 1. Gronskov, K et al. (2007). Oculocutaneous albinism. Orphanet Journal of Rare Diseases. 2 (43), p1-8. Lewis, R.A. (2000). Oculocutaneous Albinism Type 1. Available: http://www.ncbi.nlm.nih.gov/books/NBK1166/. Last accessed 22/6/2013 OMIM. http://www.omim.org/entry/606933?search=albinism&highlight=albinism. Tyrosinase, TYR. OMIM. http://www.omim.org/entry/203100?search=albinism&highlight=albinism ALBINISM, OCULOCUTANEOUS, TYPE IA; OCA1A. OMIM. http://www.omim.org/entry/606952?search=albinism&highlight=albinism. ALBINISM, OCULOCUTANEOUS, TYPE IB; OCA1B PICTURES: http://www.ojrd.com/content/2/1/43/figure/F3 http://albinismdb.med.umn.edu/oca1map.htm QUESTION 2 SUMMARY OF ARTICLE. The article” Epigenetics of major psychosis: progress, problems and perspectives” by Labrie et al, reviews the emerging field of Epigenetics in studying brain and other tissues. It also establishes a link between psychiatric diseases and role of Epigenetics and discusses the future of psychiatric Epigenetics. Linking Epigenetics and Psychiatric Diseases ( Schizophrenia and bipolar disorder) The article introduces the major psychiatric ailments which are resistant to medical or therapeutic interventions. Both SCZ and BPD are collectively known as major psychosis and is complex in nature. Extensive research has shown that these ailments are associated to the field of genetics however the progress is limited the interaction of genes with other genes and that with the environment is complex. The authors believe that epigenetic mechanisms play a major role in major psychosis which is more important than those played by the DNA sequence or the effects of environmental factors. The reason behind this is that findings about epigenetics and that of the epigenome shows that epigenetics misregulations lead to cognitive problems. Furthermore, research on epigenetics has highlighted the fact that psychiatric diseases have both heritable as well as non-heritable components. Epigenetics and Brain Function The underlying mechanisms of cognitive functioning are proper synaptic signaling and organization and it has been seen that epigenetic factors can influence these mechanisms. It has been seen in laboratory studies that active de novo methylation is essential for long-term memories and absence of methyltransferases which induce DNA de novo methyltranfer hampers long term memory, therefore covalent DNA modifications are important for cognitive functioning. Moreover changes in the histone proteins by chromatin accessibility alteration and gene transcription also effects learning and memory. Epigenetic method such as histone methylation is important to maintain proper cognitive functioning however, increases in the activity of histone deacetylase in the neurons impairs memory and learning which a result of histone deacetylation is. These studies establish that epigenetic modifications are pivotal for neuronal plasticity and proper cognition which is impaired in psychiatric diseases. The conventional paradigm of DNA+environment factor which causes psychiatric problems may be looked at while considering an epigenetic approach to the problem. Twin and family studies have showed that psychiatric diseases have a genetic influence and are often 80% heritable further establishing the need for epigenetic research on major psychosis. So far, Copy number variants, GWAS and rare DNA mutations have answered a minute fraction of question posed upon psychiatric disease heritability and on the concept of missing heritability. Missing heritability is the difference noticed between estimated epidemiological heritability and phenotypic proportion .Epigenetic heritability sheds light on the heritable nature. It is thought that missing heritability is not actually “missing” but is “hidden” across linkage disequilibrium. Conventionally epigenetics was known as the DNA and histone modifications which was transferred during mitosis but these modification were believed to have been checked and reset down the generation. Previously inheritance of epimutations was thought to be impossible however animal models have established otherwise. In this regard epigenetical similarity between monozygotic twins indicates epigenetic stability in somatic cells and accounts for a part of the missing heritability concept. Epigenetics is also the key for research on the non-heritable factors of psychiatric diseases since experiments show that environmental factors can alter the epigenetics. Epigenetic methodologies maybe employed to determine to measure the environmental effects at the molecular level. Epigenetics has introduced a new concept where in contrast to the old gene -environment paradigm concept where heritable and acquired were independent, epigenetics believes that they may be dependent too. For example, it is possible epigenetics is regulated by environmental factors and at the same time this regulation becomes heritable in nature. Though there is no data that establishes that epigenetics is a causal factor for psychiatric diseases, the vast number of experiment surely reveal that if not a causal factor epigenetics may be a risk factor in major psychosis. Epigenetic studies on SCZ and BPD Studies aimed at examining DNA methylation and their relation with psychiatric problems yielded results during the first epigenome wide study. The study revealed several DNA methylation sites in genes were found which had effect on cognitive function. Some other studies have also shown the effect of epigenetic DNA methylation on psychiatric diseases. Other studies have measured epigenetic histone modification and have linked them to development of psychiatric problems. Furthermore, epigenetics has been associated with comorbid problems like depression which is associated with major psychosis. Psychotropic medicine induce epigenetic changes. Though it is not clear whether the epigenetic changes impact psychiatric stability directly, further research needs to be conducted to determine the actual causes. The Future of Epigenetics Research Epigenetics research is different from genetic research. The instability of the epigenetic code can help understand etiology of psychiatric diseases whereas it also poses few identification problems of its own. Modified approach based on epimutations need to designed in order to ascertain association of epigenetic abnormalities and psychiatric diseases. Several approaches can help determine the causal as well as non-causal association between epigenetics and psychiatric disorders. Firstly, if an epimutations is identifies in the tissues of several patients then it can be regarded as causal but even if an epimutation is not detected, non-casualty cannot be taken into account. Secondly, the offsprings born to parents who suffer from major psychosis can be analyzed to understand DNA and histone modification and differences between patients. Furthermore, induced epimutations in animals may help monitor regulation of epigenetic mechanisms during embryogenesis as well as growth. Evaluation DNA modifications that affect human behavior can be detected experimentally, and can be both inherited and acquired during the lifetime, is a point well justified in the article. The DNA methylation noticed in the gene HCG9 with the help of bisulfate conversion and pyrosequencing. This change was seen across many tissues and thus it can be concluded that the change was either inherited or acquired before differentiation of the tissues. Again experimental analysis of GADI protein in post-mortal schizophrenic patients’ revealed that in such patients the protein was not well expressed. QUESTION 3 a. Trisomies are condition when instead of the usual pair of chromosome, a person is born with 3 copies of the chromosome and are a result of meiotic or mitotic non-disjunction.. Three trisomies that are normally seen in viable births are trisomy 21. Trisomy 18 and trisomy 13. Trisomy 21 is also known a Down syndrome and is the most common trisomy. It caused due to an extra copy of chromosome 21. Children born with this syndrome have heart defects, are mentally retarded, have hearing, visual and sometimes speech impairment. Trisomy 18 is also known as Edwards syndrome and occurs owing to the presence of an extra chromosome 18. Children born with this syndrome suffer from a number of health problems. They may develop kidney problems, heart problems or retarded physical growth. Mental retardation is also noticed in most cases. Other symptoms include physical malformations like cleft lip, small head, clubfoot, webbed toes etc. Trisomy 13 or Patau syndrome is yet another trisomy which occurs when there are 3 copies of chromosome 13. Babies born with this syndrome develop several physical problems like mental retardation, polydactyly, motor disorder, eye problems, cleft palate, deformed feet, abnormal genitals, heart defects etc. b. Aneuploidy is a type of chromosomal mutation owing to which, abnormality in the chromosomal number occurs leading to birth defects and diminished fecundity. In humans the normal chromosome number is 23 pairs ; however several factors may lead to Aneuploidy where an individual will not have the complete set of 23 chromosome pairs. They will either lake chromosome or have an extra chromosome. Aneuploidy occurs during the process of cell division during which the chromosome fails to segregate equally between the daughter cells. Therefore an organism with an abnormal chromosomal number which differs from the normal type by a 1 or 2chromosome is known as an Aneuploid. Aneuploid condition may be categorized as monosomic, disomic, trisomic and nullisomic. One of the most common mechanisms of Aneuploidy is nondisjunction. It is mechanism owing to which the chromosome fails to divide properly during meiosis giving rise to daughter cells with imbalanced chromosome. Nondisjunction takes place owing to problems with the meiotic spindle. Because of error in the spindle in meiotic I tetrad chromosome fail to separate uniformly while problems in the spindle in meiotic II leads to separation failure of the sister chromatids both of which lead to Aneuploidy. If the gametes undergo nondisjunction during the first meiotic division, all gametes are affected, half of which lack one chromosome and the other half have an extra chromosome each. If the gametes face nondisjunction during the second meiotic division, only half of the gametes are affected. Half of the affected gametes get an extra chromosome while the other half lacks one chromosome. Another mechanism for mis-segregation of chromosome is proper functioning of Merotelic kinetochore orientation. Accurate segregation of the chromosomes depends on the proper link between the kinetochores and microtubules. During this mechanism a single kinetochore attaches to microtubules emanating from opposite poles. Spindle checkpoints before anaphase fail to recognize this anomaly because appropriate kinetochore-microtubule attachment is accomplished. This causes mis-segregation and leads to Aneuploidy. c. A child with 3 copies of chromosome 21 (2 normal and 1 extra) has Down Syndrome. When during the formation of reproductive cells a part of the chromosome 21 translocates to another chromosome and gives rise to 3 copies of chromosome 21.Howevr, when an individual with the same syndrome shows 2 copies of chromosome 21 and a microchromosome and maybe regarded as a case of partial trisomy which is a result of tandem translocation where complete triplication fails and gives rise to a microchromosome mostly acrocentric. d. A balanced translocation occurs between the chromosomes 1 and chromosome 18. A child inheriting the same balanced translocation will not show any signs since all the genetic material is present in the child though the chromosomal arrangement may differ slightly. Another male child with balanced translocation between chromosome 1 and 18 maybe called a carrier for that translocation. The gametes will be of 4 different types owing to the translocation. The 4 different types of gametes are- gamete with normal chromosome 1, gamete with translocated chromosome 1, gamete with normal chromosome 18 and gamete with translocated chromosome 18. It is comprehensible that male with such different gametes is a carrier and there are chances that the offsprings from such carrier will be born with birth defects. In the diagram below we can see that the father has balanced translocation and mother is normal. Now there are 4 possibilities for the offspring. 1. The offspring will inherit the normal chromosomes and hence will be a normal. 2. The offspring may inherit the translocated chromosome from the father and thus become a carrier for balanced translocation. 3. Offspring will inherit translocated Chromosome 1 only while other chromosome are normal which means that the baby will have extra 18 and missing 1. 4. Offspring inherits translocated chromosome 18 and other chromosomes are normal. This means that the bay will have missing 18 and extra 1. The diagram is as follows: FATHER MOTHER 1 18 1 18 e. If the child with balanced translocation is a female instead of male it is not possible for her to have 4 different gametes because in oogenesis only 1 female egg is produced at a time. f. Robertsonian translocation involves exchange between acrocentric chromosomes such as chromosome numbers 13,14,15,21 and 22.In Robertsonian translocation the 2 chromosomes lose their short arms while exchange and tend to fuse together giving rise to just 45 chromosomes in an individual. Carriers of this translocation do not exhibit any abnormality; however, the offsprings of such carrier either face miscarriage or are born with genetic diseases. The major difference between balanced and Robertsonian translocation is that in the former translocation no loss or gain of genetic material is noticed whereas for the latter loss of genetic material is there. The next difference is that balanced translocations is exchange of genetic material between 2 chromosomes but in case of Robertsonian translocation only chromosome numbers 13,14,15,21 and 22 are involved. QUESTION 4 b. Considering that Mendelian segregation takes place the inheritance pattern of the disease causing bone abnormality seems to be Autosomal Dominant. At first one may think that it is an X-linked disease but Mrs. T’s uncle who inherits the gene has an unaffected daughter which would not be possible if the disease was X-linked since he had only the affected X chromosome for contribution. Therefore, studying the inheritance pattern it seems that the inherited disease is Autosomal dominant. c. The PAR region or the Pseudoautosomal regions (PAR 1 and PAR 2) in mammals are regions of homology present in the X and Y chromosomes. During meiosis especially the male meiosis, it is possible that since X and Y share a homologous region, the process of recombination takes place. Therefore if a trait has its locus in these PAR regions of homology the inheritance pattern will be altered because now a Y-linked trait maybe passed onto the daughters while an X-linked trait maybe passed onto the sons. The inheritance pattern is almost similar to that of an autosomal inheritance pattern. Females who have two gene rich X chromosomes have the need to inactivate one of X chromosome as dosage compensation. However, genes present in the PAR regions are not inactivated since both chromosome X and Y have homologous PAR regions for which no dosage compensation is needed. d. If the clinician is correct about PAR linked trait in Mrs T’s family there is 50% chance that offspring will be affected. Since Mrs. T has the effected PAR regions while her husband does not it ,is 50% likely that the affected ones will be a female or male because all offsprings are equally likely to inherit allele from the maternal side. So, Mrs. T’s gametes, will either have the crossing over (affected allele) or they might not (unaffected allele) . e. i) If the marker alleles can be denoted D1 or D2, and the trait locus can have alleles G or g, the two possible haplotypes that II.4 could transmit are D1G and D2g. ii) Considering complete independence of marker and trait the four possible haplotypes are- D1G, D2G, D1g, D2g f. i.) Assuming complete linkage- Assuming. The total number of progeny is 6 and II.4 can transmit only 2 haplotypes which are equally likely. Therefore the probability will be = 1/128 ii.) Assuming independence between the marker and the trait there can be 4 different haplotypes. Each haplotype has ? probability. Therefore since the number of offsprings is 6 the probability is = 1/16384 g. Based on my calculations of linkage probability (X) and independence probability (Y), the LOD score is X/Y= 16384/128= 128 Taking logarithm Log (128)= 2.1 h. Yes, individual III.6 is a recombinant. This means that since she is unaffected she has inherited D2G from her father owing to crossover. i. The best allele of D3126 has LOD score of 2.43 with recombination frequency of 0.04. Therefore thap distcne in centimorgans is 4 cM. 4 cM map distance is 4 megabases physical distance along the chromosome. j. Number of genes expected is given by: Number of Genes Expected= length of the interval/ gene lenght+intergene distance Taking- average gene length = 30000 bp Average intergeen-distance is 10kb Therefore, 4mb/ (30000 bp + 10 kb) Changing the 4mb into Bp we get 4,000,000 bp Changing 10kb into bp we get, 10,000 Therefore= 4,000,000/ (30000+10,000)= 100. k. The geneticists studied a diagram of this interval on the PAR, and focused on four genes listed below that might have explained the family disease if they were mutated or deleted. Suggest the best candidate gene to compare by exome sequencing in affected and non-affected family members: explain your choice. (5%) The best candidate for comparison by exome sequencing is SHOX gene which is located in the nucleus of osteogenic cells. My first choice is SHOX since it is known that shortage of SHOX owing to deletions causes limb shortening. Moreover, SHOX has just 6 exons. REFERENCES BOOKS Sanger, Warren, 2002, Medical Genetics, Boston Medical Publishing Corporation, USA. Vogel, Friedrich, 1997, Human Genetics:Problems and Approaches, Springer, UK. Westman,Judith,2006, Medical Genetics for the Modern Clinician, Lippincott Williams and Wilkins, USA. WEBSITES OMIM. http://www.omim.org/entry/190685?search=trisomy&highlight=trisomy. DOWN SYNDROME. OMIM. http://www.omim.org/entry/158250?search=trisomy&highlight=trisomy. Non-disjunction. Read More