Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-β hydroxylase deficiency

Kandemir, Nurgün; Yılmaz, Didem; Gönç, E. Nazlı; Özön, Alev; Alikaşifoğlu, Ayfer; Dursun, Ali; Özgül, Rıza Köksal

doi:10.1016/j.jsbmb.2016.03.006

Cited by 28 publications

(17 citation statements)

References 22 publications

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“…We found that 41 compound heterozygotes or homozygotes for select missense or nonsense mutations-namely P49L, R141Q, W260X, G267S, L299P, T318M, T318R, A331V, Q356X, A368D, R374Q, V441G, G444D, G446V, and R448H-present with moderate to severe classic CAH because of 11β-hydroxylase, confirming prior results (3,(14)(15)(16)(17)(22)(23)(24). These patients were mainly from Croatia, Tunisia, Africa, Turkey, and Saudi Arabia.…”

Section: Discussionsupporting

confidence: 88%

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Khattab

Haider

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.steroid hormones | missense mutations | classic CAH | ambiguous genitalia C ongenital adrenal hyperplasia (CAH) is a Mendelian disorder transmitted as an autosomal recessive trait. The most prevalent form of CAH arises from steroid 21-hydroxylase enzyme deficiency, accounting for ∼90-95% of all cases (1, 2). In contrast, CAH caused by steroid 11β-hydroxylase deficiency is considerably rare, with a prevalence of 5-8% (3), from which we estimate an overall frequency of 1 in 100,000 live births.Two homologous enzymes, 11β-hydroxylase and aldosterone synthase, are encoded by the CYP11B1 and CYP11B2 genes, respectively. The two genes are 40-kb apart, each comprising nine exons and mapped to chromosome 8q21-22 (3, 4) (Fig. 1A). In contrast to CYP21A2 and its CYP21A1P pseudogene, CYP11B1 and CYP11B2 are both active and do not have a pseudogene. The two encoded homologs, however, have distinct functions in cortisol and aldosterone synthesis, respectively (3). In the zona fasciculata, 11β-hydroxylase converts 11-deoxycortisol and 11-deoxycorticosterone to cortisol and corticosterone, respectively, and is regulated by adrenocorticotropic hormone secreted by the pituitary. In contrast, in the zona glomerulosa aldosterone synthase converts corticosterone to aldosterone with the intermediate production of 18-hydroxycorticosterone. These latter conversions are controlled mainly by the renin angiotensin II system and serum potassium concentration (3).Deficiency of 11β-hydroxylase prevents the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. This results in high levels of 11-deoxycortisol and 11-deoxycorticosterone, respectively, which are shunted into the androgen synthesis pathway, resulting in high levels of the androgenic steroid, androstenedione. Female newborns are thus profoundly virilized and exhibit significant masculinization of the ex...

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Section: Discussionsupporting

confidence: 88%

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Khattab

Haider

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

112

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“…In contrast, in a Turkish cohort, the c.954G>A splice site mutation was the most frequent, with an allele frequency of 14.6%, followed by p.Arg141*, with a frequency of 12.5% and p.Leu299Pro, p.Gln189Hisfs*70, and IVS8+5G>C, each with an allele frequency of 8.3% [62]. Uniparental disomy is a recognized phenomenon causing disease when one parent is non-carrier and other parent is a carrier of disease mutation and was recently reported in a neonate diagnosed with classic 11βOHD with only a mutation identified in the father [82].…”

Section: Classic 11βohdmentioning

confidence: 70%

“…There are up to 13 mutations associated with NC 11βOHD in the literature (Table 2) [32,38,62,[83][84][85]. The degree of enzyme activity compromise associated with NC 11βOHD is similar to that seen in NC 21OHD (20-50%) [14].…”

Section: Classic 11βohdmentioning

confidence: 86%

“…It is difficult to predict the actual disruptive effects of mutations that affect enzyme activity and the clinical phenotype. This variability in patient genotypes is related to the wide range of clinical presentation among patients with 11βOHD [62]. In 21OHD on the other hand, the genotypephenotype correlation is generally considered good [63][64][65], particularly for the genotypes corresponding to SW and NC CAH, while it is more unpredictable in the SV phenotype [66,67].…”

Section: Molecular Geneticsmentioning

confidence: 99%

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Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

2016

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Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a rare autosomal recessive genetic disorder. It is caused by reduced or absent activity of 11β-hydroxylase (CYP11B1) enzyme and the resultant defects in adrenal steroidogenesis. The most common clinical features of 11 beta-hydroxylase deficiency are ambiguous genitalia, accelerated skeletal maturation and resultant short stature, peripheral precocious puberty and hyporeninemic hypokalemic hypertension. The biochemical diagnosis is based on raised serum 11-deoxycortisol and 11-deoxycorticosterone levels together with increased adrenal androgens. More than 100 mutations in CYP11B1 gene have been reported to date. The level of in-vivo activity of CYP11B1 relates to the degree of severity of 11 beta-hydroxylase deficiency. Clinical management of 11 beta-hydroxylase deficiency can pose a challenge to maintain adequate glucocorticoid dosing to suppress adrenal androgen excess while avoiding glucocorticoid-induced side effects. The long-term outcomes of clinical and surgical management are not well studied. This review article aims to collate the current available data about 11 beta-hydroxylase deficiency and its management.

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“…There has been limited evidence until recently regarding genotype-phenotype relationships in patients with 11βOHD owing to the rarity of the disease and the wide variability in the clinical presentation [10]. A large international cohort study of 108 patients from 11 countries examined the clinical, genetic, and structural effects of CYP11B1 mutations.…”

Section: Discussionmentioning

confidence: 99%

Two rare forms of congenital adrenal hyperplasia, 11β hydroxylase deficiency and 17-hydroxylase/17,20-lyase deficiency, presenting with novel mutations

2018

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Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-β hydroxylase deficiency

Cited by 28 publications

References 22 publications

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Two rare forms of congenital adrenal hyperplasia, 11β hydroxylase deficiency and 17-hydroxylase/17,20-lyase deficiency, presenting with novel mutations

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