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ANALIZA UTICAJA MUTACIJE p.Gln226Lys U GENU ZA FENILALANIN HIDROKSILAZU
                  (PAH) NA STRUKTURU I FUNKCIJU PROTEINA PAH POMOĆU BIOINFORMATIĈKIH
                                                        SOFTVERA

                     ANALYSIS OF THE IMPACT OF p.Gln226Lys MUTATION IN THE PHENYLALANINE
                  HYDROXYLASE GENE (PAH) ON THE STRUCTURE AND FUNCTION OF PAH PROTEIN
                                           USING BIOINFORMATICS SOFTWARE

               Autor: Jovana Lazarević Užička gimnazija-Ivgodina Regionalni centar za talente Beograd II

               Mentor: Dr Kristel Klaassen, naučni saradnik


                                                          REZIME
               Fenilketonurija  (PKU)  je  monogenska  bolest  koja  predstavlja  jedan  od  najčešćih  naslednih
               poremećaja  metabolizma  aminokiselina.  Nasleđuje  se  autozomno  recesivno  i  uzrokovana  je
               mutacijama  u  genu  za  fenilalanin  hidroksilazu  (PAH).  Mutacije  u  genu  PAH  dovode  do
               izmenjene  strukture  i/ili  funkcije  enzima,  koji  za  krajnju  posledicu  ima  tešku  i  irverzibilnu
               mentalnu  retardaciju. Cilj ovog rada bila je predikcija efekta mutacije p.Gln226Lys u genu PAH
               korišćenjem različitih  bioinformatičkih softvera.  PolyPhen-2, SIFT i  MutPred su  krorišćeni  za
               predikciju  efekta  mutacija  na  strukturu  i  funkciju  proteina.  Proteinski  model  je  analiziran  uz
               pomoć Swiss-PdbViewer programa. Korišćenjem Clustal Omega softvera ispitivana je evolutivna
               očuvanost izmenjenih  aminokiselina. Svi  korišćeni  softveri ukazuju  da se radi  o mutaciji  koja
               najverovatnije dovodi do teške kliničke slike. Rezultate je neophodno potvrditi funkcionalnom
               analizom mutacije.
               Kljuĉne reĉi: bioinformatički softveri, gen za fenilalanin hidroksilazu, fenilketonurija, mutacije


                                                         SUMMARY
               Phenylketonuria (PKU)  is  a monogenic disease  and presents  one of the most common inborn
               disorders of amino acid metabolism. It is inherited in an autosomal recessive manner and it is
               caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutations in the PAH gene
               lead to an altered structure and/or function of the enzyme, thus leading to elevated level of blood
               phenylalanine, which finally results in severe and irreversible mental retardation. The aim of this
               study  was  to  predict  the  effect  of  p.Gln226Lys  mutation  in  the  PAH  gene  using  various
               bioinformatics software programs. PolyPhen-2, SIFT and MutPred were used to predict the effect
               of mutations on the structure and function of the protein. The protein model was analyzed with
               Swiss-PdbViewer program. The evolutionary preservation of altered amino acids was tested by
               using  Clustal  Omega  software.  All  used  software  programs  suggest  that  the  mutation  most
               probably leads to severe clinical manifestations. The results ought to be confirmed by performing
               functional analysis of the mutation.
               Key words: bioinformatics software programs, mutations, phenylalanine hydroxylase gene,
               phenylketonuria
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