hrp0095p1-208 | Adrenals and HPA Axis | ESPE2022

Targeting melanocortin type 2 receptor (MC2R) with peptides for the treatment of congenital adrenal hyperplasia

V Pandey Amit , Singh Shripriya , Parween Shaheena

Congenital adrenal hyperplasia (CAH) is a common disorder of steroid production mainly caused by a mutated CYP21A2 gene, causing 21-hydroxylase deficiency (21OHD). CAH due to 21OHD requires lifelong mineralocorticoid (MC) and glucocorticoid (GC) therapy. But, from the location of the enzyme block in the steroid production and increase of adrenocorticotropic hormone (ACTH) which stimulates the melanocortin type 2 receptor (MC2R) in the adrenal, excessive adrenal androgen produc...

hrp0092fc3.3 | Multi-system Endocrine Disorders | ESPE2019

Variability in Drug Metabolizing Cytochrome P450 Activities Caused by Human Genetic Variations in NADPH Cytochrome P450 Oxidoreductase (POR)

Velazquez Maria Natalia Rojas , Parween Shaheena , Pandey Amit V

Background: A broad spectrum of human diseases, including abnormalities in steroidogenesis, are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR) (1-2). Cytochrome P450 proteins perform several reactions, including metabolism of steroids, drugs and other xenobiotics. Therefore, genetic variations in POR can impact many different metabolic pathways by changing the activities of cytochromes P450 (1). In 2004 the first human patients with defe...

hrp0092rfc15.3 | Late Breaking Abstracts | ESPE2019

Metformin Treatment Affects ACTH Receptor Activation and Downstream Signaling: A Potential Treatment for ACTH Excess Disorders and Management of Hyperandrogenic States

Parween Shaheena , Pandey Amit V. , Flueck Christa E.

Background: The peptide hormone adrenocorticotropin (ACTH or Corticotropin) is a major component of the stress response system in the Hypothalamus-Pituitary-Adrenal (HPA) axis. Under stress, it is secreted from the anterior pituitary and stimulates cortisol production from the adrenal cortex. Changes in ACTH production or action are associated with multiple disease conditions. In clinical situations like Cushing's disease, ectopic ACTH syndrome and congeni...

hrp0089fc1.3 | Adrenals & HPA Axis | ESPE2018

Targetting the Binding of ACTH to the Melanocortin Receptor by Structure Modeling and Design of Peptide antagonists to Block Excess Androgens in 21-hydroxylase Deficiency

Parween Shaheena , Fluck Christa E , Pandey Amit V

Background: The adrenocorticotropic hormone (ACTH) is a 39 amino acid polypeptide secreted by the anterior pituitary and regulates cortisol secretion from the adrenal cortex. Cortisol has negative feedback and regulates the synthesis and secretion of the ACTH. Excess ACTH is associated with a wide range of diseases including congenital adrenal hyperplasia (CAH). Classic CAH due to the 21-hydroxylase (CYP21A2) deficiency causes a reduction or loss of cortisol synthesis. Here th...

hrp0089fc14.3 | Multisystem Endocrine Disorders | ESPE2018

Regulation of Salt, Sugar and Sex Steroids in Humans by Genetic Variations in NADPH Cytochrome P450 Oxidoreductase (POR) Identified in 1000 Genome Samples

Pandey Av Amit V , Udhane Sameer S , Parween Shaheena

A broad spectrum of human diseases, including abnormalities in steroidogenesis, are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR) (1-4). Human POR is a diflavin reductase that transfers electrons from NADPH to small molecules, non-P450 redox partners and cytochrome P450 proteins in the endoplasmic reticulum. Cytochrome P450 proteins perform a very wide range of reactions, including metabolism of steroids, drugs and other xenobiotics. Therefore, genetic ...

hrp0089rfc1.2 | Adrenals & HPA Axis | ESPE2018

Changes in CYP19A1 and CYP3A4 Activities due to Population Genetic Variations in Human P450 Oxidoreductase

Parween Shaheena , Udhane Sameer S , Kagawa Norio , Pandey Amit V

Background: Cytochromes P450 proteins metabolize several steroid hormones, drugs and xenobiotics. All cytochromes P450s in the endoplasmic reticulum require P450 oxidoreductase (POR) for their catalytic activities. Earlier it has been shown that mutations in POR cause metabolic disorders of steroid hormone biosynthesis and also affect some drug metabolizing P450 activities. We aimed to characterize the mutations identified in nonclinical samples to access their effects on ster...

hrp0086p1-p362 | Gonads & DSD P1 | ESPE2016

Aromatase Activity is Disrupted by Mutations in P450 Oxidoreductase

Udhane Sameer S. , Parween Shaheena , Pandey Amit V.

Background: The steroidogenic enzyme aromatase (CYP19A1) is a protein located in endoplasmic reticulum (ER) that catalyzes the conversion of androgens to estrogens. Both deficiency and excess of aromatase activity lead to disease states implicating its role in human biology. Cytochrome P450 (CYP) enzymes in ER use reduced nicotinamide adenine dinucleotide phosphate through cytochrome P450 oxidoreductase (POR) for their metabolic activities. Mutations in POR cause disorders of ...

hrp0084fc10.4 | Perinatal Endocrinology | ESPE2015

Effect of P450 Oxidoreductase Variants on Metabolism by Cytochrome P450 Proteins

Parween Shaheena , Udhane Sameer S , Pandey Amit V

Background: A broad spectrum of human diseases including abnormalities in steroidogenesis is caused by mutations in the NADPH P450 oxidoreductase (POR). POR transfers electrons from NADPH to several small molecules, non-P450 redox partners and all microsomal cytochrome P450 proteins. POR disruption affects all partners with disastrous consequences and POR knock-out mice are embryonically lethal. A number of POR mutations and polymorphisms have been characterized from patients ...

hrp0089p1-p141 | GH & IGFs P1 | ESPE2018

Autosomal Dominant Growth Hormone Deficiency due to a Novel c.178G>A Mutation in the GH1 Gene Causing Instability of the Mutant GH Protein (p.Ala34Thr)

Miller Bradley , Tan Jimmy , Parween Shaheena , Eble Andree , Ternand Christine , Gregory Louise , Dattani Mehul , Pandey Amit

Background: The most frequent cause of familial growth hormone deficiency (GHD) is Type II autosomal dominant GHD (isolated GHD type II) due to several heterozygous GH1 mutations.Method: Genomic DNA from patients with familial GHD was enriched for the coding exons using hybrid capture technology and GH1 was sequenced using Next Generation Sequencing technology. Plasmids containing genes for WT and A34T GH1 were transfected into NCI HEK2...

hrp0089p1-p017 | Adrenals and HPA Axis P1 | ESPE2018

Biochemical, Genetic and Molecular Characterization of a Novel P399_E401Dup Mutation in P450 Oxidoreductase (POR) Altering Several Enzymatic Activities in a Patient with a 46,XX DSD Phenotype at Birth

Boettcher Claudia , Parween Shaheena , Korsch Eckhard , Hartmann Michaela F , Udhane Sameer , Kagawa Norio , Fluck Christa E , Wudy Stefan A , Pandey Amit V

Background: P450 oxidoreductase (POR) mutations can present with disordered sexual development (46,XX virilisation as well as 46,XY under-masculinisation), perturbed steroidogenesis and mild to severe skeletal malformations. As POR is an obligate electron donating cofactor to many P450s, and as this interaction may vary from partner to partner, the phenotypic spectrum of PORD is extremely broad. Therefore, to characterize novel POR mutations, specific testing is required.<...