Deficiency Of Enzyme 21-hydroxylase Research Articles

Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations

Deficiency of 21-hydroxylase enzyme (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction and functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V, and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of CYP21A2 deficiency.

OR25-01 Durable CYP21A2 Gene Therapy in Non-Human Primates for Treatment of Congenital Adrenal Hyperplasia

Severe Congenital Adrenal Hyperplasia (CAH) is most commonly caused by genetic defects in the CYP21A2 gene, which leads to a deficiency of 21-hydroxylase enzyme and disruption in the biosynthesis of Adrenal corticosteriods. Despite treatment with corticosteroids, patients remain at significant risk for adrenal crisis, experiencing a 3-fold higher mortality rate than age matched controls. They also suffer from significant infertility, bone, metabolic, and cardiovascular disease, and hyperandrogenism in women leading to genital abnormalities, hirsutism, and other complications. We are developing an AAV5- based gene therapy (BBP-631) that will provide a functional copy of the CYP21A2 gene to the adrenal glands of CAH patients. To determine the durability of this therapy we treated cynomolgus monkeys with increasing doses of BBP-631 via intravenous injection. At 4-, 12- and 24-weeks post treatment, expression of hCYP21A2 mRNA and vector genome copies (VGC) in the adrenals and other peripheral tissues was measured. VGC was present in the liver and adrenals at 4 weeks, with durable detection through 24 weeks and total vg levels were dose dependent. hCYP21A2 RNA expression in adrenal and liver tissues was also dose dependent and continued to increase from 4 weeks through 12 weeks. There were no adverse safety signals in any of the treated animals. This data combined with efficacy data of BBP-631 in a Cyp21-/- mouse model supports our continued clinical development of BBP-631 as a treatment for congenital adrenal hyperplasia.

Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: An Update on Genetic Analysis of CYP21A2 Gene.

Congenital Adrenal Hyperplasia is a group of genetic autosomal recessive disorders that affects adrenal steroidogenesis in the adrenal cortex. One of the most common defects associated with Congenital Adrenal Hyperplasia is the deficiency of 21-hydroxylase enzyme, responsible for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. The impairment of cortisol and aldosterone production is directly related to the clinical form of the disease that ranges from classic or severe to non-classic or mild late onset. The deficiency of 21-hydroxylase enzyme results from pathogenic variants on CYP21A2 gene that, in the majority of the cases, compromise enzymatic activity and are strongly correlated with the clinical severity of the disease. Due to the exceptionally high homology and proximity between the gene and the pseudogene, more than 90% of pathogenic variants result from intergenic recombination. Around 75% are deleterious variants transferred from the pseudogene by gene conversion, during mitosis. About 20% are due to unequal crossing over during meiosis and lead to duplications or deletions on CYP21A2 gene. Molecular genetic analysis of CYP21A2 variants is of major importance for confirmation of clinical diagnosis, predicting prognosis and for an appropriate genetic counselling. In this review we will present an update on the genetic analysis of CYP21A2 gene variants in CAH patients performed in our department.

Determinants of growth and final height outcome in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia(CAH)is a family of autosomal recessive disorders caused by the loss or severe decrense in activitv in one of the steroidogenie enzymes involved in cortisol biosynthesis.The cortisol synthetic block leads to corticotropin stimulation of the adrenal cortex.with accumulatiOn of cortisol precursors that are diverted to sex hormone biosynthesis.The most common CAH is 21-OHD due to deficiency of the enzyme 21-hydroxylase.It is distinguished in classical(C-CAH)and non-classical form(NC-CAH),and it is also one of the most eomnon autosomal recessive inherited disorders in human.The goal of therapy in CAH is to replace the missing glucocorticoids and mineralocorticoids,thereby suppressing eorticotropin concentrations and normalizing adrenal androgens, a8 well as to enable normal growth and skeletal maturation.Nonetheless.growth is a key problem in CAH because patients often fail to reach their target height,and the average heights are shorter than the general population,relating both to the underlying disease and its treatment.This paper review the literature on growth and final height outcome,considering the factors related tO diagnosis and treatment which are known to affect height outcome.Current strategies to optimize height outcome are indicated and future treatment strategies as well. Key words: Congenital adrenal hyperplasia; 21-hydroxylase deficiency; Growth; Final height