Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population

Alswailem, Meshael; Alzahrani, Ohoud; Alhomaidah, Doha S.; Alasmari, Rahma; Qasem, Ebtesam; Murugan, Avaniyapuram Kannan; Alsagheir, Afaf; Brema, Imad; Abbas, Bassam Ben; Almehthel, Mohammed; Almeqbali, Ali; Alzahrani, Ali S.

doi:10.1016/j.mce.2017.08.022

Cited by 13 publications

(11 citation statements)

References 45 publications

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“…P30L is localized at the N terminus of the protein responsible for the orientation toward the membrane of the endoplasmatic reticulum gene conversion, I2 splice, V281L, and I172N [7,14,16,37,45]. In populations with consanguinity the variability is lower compared with admixed populations [64,65]. Different reports show that the P30L is not among the most common mutations.…”

Section: Prevalence Of P30l Mutationmentioning

confidence: 99%

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Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020

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Despite numerous studies in the field of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, some clinical variability of the presentation and discrepancies in the genotype/phenotype correlation are still unexplained. Some, but not all, discordant phenotypes caused by mutations with known enzyme activity have been explained by in silico structural changes in the 21-hydroxylase protein. The incidence of P30L mutation varies in different populations and is most frequently found in several Central and Southeast European countries as well as Mexico. Patients carrying P30L mutation present predominantly as non-classical CAH; however, simple virilizing forms are found in up to 50% of patients. Taking into consideration the residual 21-hydroxulase activity present with P30L mutation this is unexpected. Different mechanisms for increased androgenization in patients carrying P30L mutation have been proposed including influence of different residues, accompanying promotor allele variability or mutations, and individual androgene sensitivity. Early diagnosis of patients who would present with SV is important in order to improve outcome. Outcome studies of CAH have confirmed the uniqueness of this mutation such as difficulties in phenotype classification, different fertility, growth, and psychologic issues in comparison with other genotypes. Additional studies of P30L mutation are warranted.

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Section: Prevalence Of P30l Mutationmentioning

confidence: 99%

“…The most common mutations are deletion or large gene conversion, I2 splice, V281L, and I172N [ 7 , 14 , 16 , 37 , 45 ]. In populations with consanguinity the variability is lower compared with admixed populations [ 64 , 65 ]. Different reports show that the P30L is not among the most common mutations.…”

Section: Prevalence Of P30l Mutationmentioning

confidence: 99%

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020

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“…On the other hand, 17α-hydroxylase catalyze progesterone into 17-OHP, and the deficiencies of 17α-hydroxylase led to the decrease of cortisol and a compensatory increase of 11-deoxycorticosterone (DOC). DOC excess causes hypertension and hypokalemia (Auchus, 2017; Sun et al, 2017; Alswailem et al, 2018). Complete deficiency of 17α-hydroxylase and 17,20-lyase activity could be used as a potential biomarker for future 17-OHD screenings.…”

Section: Discussionmentioning

confidence: 99%

A Novel Compound Heterozygous CYP17A1 Variant Causes 17α-Hydroxylase/17, 20-Lyase Deficiency

et al. 2019

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Background: Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive diseases characterized by enzyme deficiencies, within steroid hormone anabolism, which lead to disorders in cortisol synthesis. The 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is an uncommon form of CAH caused by variants in the CYP17A1 gene. Aims: We report a novel compound heterozygous CYP17A1 variant and its association with the pathogenesis of 17-OHD. Methods: The patient was assessed for medical history, clinical manifestations, physical examination, laboratory examination, karyotype analysis, and adrenal computed tomography. Mutation screening was conducted using whole-exome sequencing (WES) and Sanger sequencing. The wild-type and mutant CYP17A1 complementary DNAs (cDNAs) were amplified and cloned into a pcDNA3.1(+) vector. These plasmids were transfected transiently into HEK-293T cells. Quantitative PCR and Western blotting analysis were performed to measure the expression level of P450c17. An enzymatic activity assay was conducted to measure the content of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone (DHEA) in medium using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: The proband was characterized by 17-OHD with rhabdomyolysis, hypokalemia, and adrenal insufficiency. Novel compound heterozygous variants of the CYP17A1 gene (c.1304T > C/p.Phe435Ser and c.1228delG/p.Asp410Ilefs*9) were identified. The enzymatic activity assay revealed that this variant resulted in a complete deficiency of 17α-hydroxylase and 17,20-lyase activity. This was consistent with the hormonal characteristics of the proband’s blood. Conclusions: These results suggest that the compound heterozygous variant of c.1304T > C and c.1228delG of the CYP17A1 gene can lead to 17-OHD. Our findings thus provide a novel insight into the clinical evaluations and molecular basis of 17-OHD.

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“…The human type I isoenzyme 3βHSD is the isoenzyme, encoded by HSD3B1 gene and is expressed in peripheral tissue including skin, mammary glands, and placenta [9,11,14]. It has 372 amino acids and shares more than 90% homology with the type II isoenzyme [27,28]. The human type I isoenzyme 3βHSD catalyzes transformation of DHEA into sex steroids including testosterone and estradiol [9].…”

Section: Pathophysiologymentioning

confidence: 99%

Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency

2019

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Purpose 3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) is a very rare variant of congenital adrenal hyperplasia (CAH) causing less than 0.5% of all CAH. The aim was to review the literature. Methods PubMed was searched for relevant articles. Results 3βHSD2D is caused by HSD3B2 gene mutations and characterized by impaired steroid synthesis in the gonads and the adrenal glands and subsequent increased dehydroepiandrosterone (DHEA) concentrations. The main hormonal changes observed in patients with 3βHSD2D are elevated ratios of the Δ5-steroids over Δ4-steroids but molecular genetic testing is recommended to confirm the diagnosis. Several deleterious mutations in the HSD3B2 gene have been associated with saltwasting (SW) crisis in the neonatal period, while missense mutations have been associated with a non-SW phenotype. Boys may have ambiguous genitalia, whereas girls present with mild or no virilization at birth. The existence of non-classic 3βHSD2D is controversial. In an acute SW crisis, the treatment includes prompt rehydration, correction of hypoglycemia, and parenteral hydrocortisone. Similar to other forms of CAH, glucocorticoid and mineralocorticoid replacement is needed for long-term management. In addition, sex hormone replacement therapy may be required if normal progress through puberty is failing. Little is known regarding possible negative long-term consequences of 3βHSD2D and its treatments, e.g., fertility, final height, osteoporosis and fractures, adrenal and testicular tumor risk, and mortality. Conclusion Knowledge is mainly based on case reports but many long-term outcomes could be presumed to be similar to other types of CAH, mainly 21-hydroxylase deficiency, although in 3βHSD2D it seems to be more difficult to suppress the androgens.

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Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population

Cited by 13 publications

References 45 publications

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

A Novel Compound Heterozygous CYP17A1 Variant Causes 17α-Hydroxylase/17, 20-Lyase Deficiency

Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency

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