Cytochrom P450 oxidoreduktáza: Strukturálně funkční studie. Molekulární patologie Antley - Bixlerova syndromu.

ABSTRAKTNADPH-P450 oxidoreduktáza (POR) je membránový flavoprotein, který transportuje elektrony na široké spektrum hemoproteinů, řada z nich hraje podstatnou úlohu v metabolizmu xenobiotik a steroidů. Vzhledem k nezastupitelné roli POR v metabolismu léků je v posledních letech pozorován zvýšený zájem o analýzu genu POR, zejména v oblasti farmakogenomiky. Mutace v genu POR způsobují onemocnění, které souborně nazýváme POR deficience. Toto onemocnění se projevuje širokým spektrem fenotypových projevů sahajících od poruch steroidogenéze až po kosterní malformace známé jako Antley-Bixlerův syndrom (ABS). Cílem předložené práce je analýza genu POR u pacientů s podezřením na POR deficienci a poprvé v běžné české a židovské populaci. Analyzovali jsme 644 alel nepříbuzných českých jedinců a 1128 alel v populaci židovské, 330 alel Aškenázů, 798 alel Sefardů. Následně byl studován vliv vybraných nových genetických variant na aktivitu POR proteinu. Definovali jsme frekvence alel genu POR v obou populacích, popsali jsme 14 nových variant vedoucích k aminokyselinovým záměnám POR proteinu a prozkoumali jsme dvě z nich s cílem určit jejich vliv na aktivitu proteinu. Dostupnost struktury lidské POR umožnila modelování nově popsaných variant a popis defektu na molekulární úrovni. Analýza genu POR byla následně v laboratoři...NADPH-P450 oxidoreductase (POR) is a membrane bound flavoprotein that donates electrons to a wide spectrum of heme-containing proteins, among which are several steroidogenic and many xenobiotics-metabolizing enzymes. Given the important role of POR protein in drug metabolism and pharmacogenomics, there is a particular need to understand the contributions of POR genetic variants to these processes. Mutations in POR gene cause a disorder called POR deficiency, which manifests with a wide phenotypic spectrum ranging from disordered steroidogenesis to skeletal malformation, namely, Antley-Bixler syndrome (ABS). The aim of the present work was to investigate the POR gene in patients suspected to have POR deficiency syndrome from Czech Republic and to perform genotyping in Czech and Jewish control populations. We analyzed 644 alleles in unrelated individuals from the general Czech population and 1128 alleles in Jewish population, where 330 alleles were of Askhenazi and 798 of Sephardic Jews. We have also studied the impact of selected new genetic variants on POR activity and identified fourteen amino acid variations, two of which we have studied in detail to establish their influence on POR activity. Using the available human POR three-dimensional structure, we then modelled the newly identified variants...Klinika pediatrie a dědičných poruch metabolismu 1. LF UK a VFNDepartment of Paediatrics and Inherited Metabolic Disorders First Faculty of MedicineFirst Faculty of Medicine1. lékařská fakult

Hereditary Hemochromatosis, the most common genetic disorder in the caucasian population

Katedra antropologie a genetiky člověkaDepartment of Anthropology and Human GeneticsFaculty of SciencePřírodovědecká fakult

Cytochrome P450 oxidoreductase: Structurally functional study. Molecular pathology of Antley-Bixler syndrome.

NADPH-P450 oxidoreductase (POR) is a membrane bound flavoprotein that donates electrons to a wide spectrum of heme-containing proteins, among which are several steroidogenic and many xenobiotics-metabolizing enzymes. Given the important role of POR protein in drug metabolism and pharmacogenomics, there is a particular need to understand the contributions of POR genetic variants to these processes. Mutations in POR gene cause a disorder called POR deficiency, which manifests with a wide phenotypic spectrum ranging from disordered steroidogenesis to skeletal malformation, namely, Antley-Bixler syndrome (ABS). The aim of the present work was to investigate the POR gene in patients suspected to have POR deficiency syndrome from Czech Republic and to perform genotyping in Czech and Jewish control populations. We analyzed 644 alleles in unrelated individuals from the general Czech population and 1128 alleles in Jewish population, where 330 alleles were of Askhenazi and 798 of Sephardic Jews. We have also studied the impact of selected new genetic variants on POR activity and identified fourteen amino acid variations, two of which we have studied in detail to establish their influence on POR activity. Using the available human POR three-dimensional structure, we then modelled the newly identified variants..

Cytochrome P450 oxidoreductase: Structurally functional study. Molecular pathology of Antley-Bixler syndrome.

NADPH-P450 oxidoreductase (POR) is a membrane bound flavoprotein that donates electrons to a wide spectrum of heme-containing proteins, among which are several steroidogenic and many xenobiotics-metabolizing enzymes. Given the important role of POR protein in drug metabolism and pharmacogenomics, there is a particular need to understand the contributions of POR genetic variants to these processes. Mutations in POR gene cause a disorder called POR deficiency, which manifests with a wide phenotypic spectrum ranging from disordered steroidogenesis to skeletal malformation, namely, Antley-Bixler syndrome (ABS). The aim of the present work was to investigate the POR gene in patients suspected to have POR deficiency syndrome from Czech Republic and to perform genotyping in Czech and Jewish control populations. We analyzed 644 alleles in unrelated individuals from the general Czech population and 1128 alleles in Jewish population, where 330 alleles were of Askhenazi and 798 of Sephardic Jews. We have also studied the impact of selected new genetic variants on POR activity and identified fourteen amino acid variations, two of which we have studied in detail to establish their influence on POR activity. Using the available human POR three-dimensional structure, we then modelled the newly identified variants..