1. Faculdade de Medicina da Universidade de Coimbra Curso de Medicina 1º Ano Ano lectivo 2009/2010

2. Splicing In splicing, introns of pre-mRNA are removed and exons are joined In splicing there are two main control elements: splicing enhancers and splicing silencers. In genetics, splicing can occur in different molecules: – mRNA – rRNA

3. Introns are removed by enzimes consisting of a protein/RNA complex (S PLICEOSSOME ) a complex formed by snRNAs associated with proteins. associated with 6 to 10 proteins in small nuclear ribonucleoprotein particles (snRNPs)

4. Alternative Splicing - Process by which the exons of the RNA produced by transcription of a gene (a primary gene transcript or pre-mRNA) are reconnected in multiple ways during RNA splicing. - The resulting different mRNAs may be translated into different protein isoforms; thus, a single gene may code for multiple proteins.

5. There are some errors in the splicing process that may cause some diseases in human body. Splicing in the Disease Mutation of the splice site Displacement of the splice site - Results in lost of function of that site Leads to inclusion or exclusion of more genetic material than expected

6. Mutations Cis-acting mutationsTrans-acting mutations Defective splicing that causes disease. considered to be DNA sequences that, via transcription factors or other trans-acting elements or factors, regulate the expression of genes on the same chromosome DNA sequence that contains a gene. This gene codes for a protein that will be used in the regulation of another target gene.

7. Familial isolated growth hormone deficiency type II (IGHD II) Cis-acting mutations growth hormone gene (GH-1). Frasier syndromeWT-1 gene Frontotemporal dementia and Parkinsonism linked to Chromosome 17 (FTDP-17) MAPT gene Atypical cystic fibrosisCFTR gene

8. Talassemia Is an inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Thalassa is Greek for the sea, Haema is Greek for blood. The disease was particularly prevalent in Mediterranean populations. The disorder results in excessive destruction of red blood cells, which leads to anemia.

9. The thalassemias are classified according to which chain of the hemoglobin molecule is affected. So there are two main forms of the disease: -α thalassemia - production of the α globin chain is affected -β thalassemia production of the β globin chain is affected.

10. Beta thalassemias are due to mutations in the HBB gene on chromosome 11 there is a relative excess of α chains these bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates. The α thalassemias involve the genes HBA1 and HBA2 It is also connected to the deletion of the 16p chromosome Alpha thalassemias Beta thalassemias

11. Treatment for Thalassemia includes chronic transfusion therapy People with thalassemia are more likely to get infections so they should get an annual flu shot and the pneumonia vaccine to help prevent infections. Folic Acid is a B vitamin that helps build red blood cells. People with thalassemia should take folic acid supplements. Researchers are also studying other treatments, such as gene therapy and fetal hemoglobin. (Persons who receive significant numbers of blood transfusions need a treatment called chelation therapy to remove excess iron from the body.)

13. Conclusions As many diseases are connected to these splice-site alterations, it will be extremely useful to know more and more about these molecular mechanisms that control this splicing pathways in order to diagnose, and consequently, treat these human diseases.

14. Bibliografia http://www.answers.com/topic/gene ALBERTS, Bruce et all (2002) Molecular Biology fo the Cell (4 th edition) Garland Science: New York http://www.web-books.com/MoBio/Free/Ch5A4.htm http://www.sumanasinc.com/webcontent/animation/content/mRNAsplicing.html http://carmelab.huji.ac.il/Teaching/Etgar/Wang_Cooper_2007.pdf http://www.gtmb.org/VOL5A/pdf/02%20Stamn%20et%20al,%209-30.pdf