A Novel Point Mutation in P450c17 (CYP17) Causing Combined 17α-Hydroxylase/17,20-Lyase Deficiency

Brooke, Antonia; Taylor, Norman; Shepherd, J. H.; Gore, M.; Ahmad, Tanya; Lin, Luke; Rumsby, Gill; Papari-Zareei, Mahboubeh; Auchus, Richard J.; Achermann, John C.; Monson, John P.

doi:10.1210/jc.2005-2653

Cited by 40 publications

(36 citation statements)

References 21 publications

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“…The substitution of arginine to glutamine in this key substrate binding region of the P450c17 protein, results in remarkable changes in the topology of the enzyme. Our results confirm the study of Brooke et al [2006], implying that these punctual changes in the amino acid sequence lead to complete function loss. By the substitution of a charged amino acid such as arginine to an uncharged like glutamine, there are substantial alterations in the interaction of the alpha-helical domain and the beta-sheet domain, essential for stabilization of the substrate binding conformation site.…”

Section: Discussionsupporting

confidence: 89%

“…The spectrum of stages of breast development but also responses to estradiol treatment in this group of patients seems to be relatively wide [Turan et al, 2009]. In the female 46,XX patient with the identical CYP17A1 mutation, breast development neither at baseline nor after treatment follow-up has been documented [Brooke et al, 2006], and no conclusion about the association between this mutation and breast development can be drawn.…”

Section: Discussionmentioning

confidence: 83%

“…There are 3 other cases of mutations affecting this particular amino acid site which lead to 46,XY DSD [Laflamme et al, 1996;Brooke et al, 2006]. One of them describes the substitution of arginine to tryptophan in 2 siblings presenting with 46,XY DSD, and the other reports the same R96Q mutation in a 46,XX female patient.…”

Section: Discussionmentioning

confidence: 99%

“…In most cases, these mutations lead to major changes in the primary amino acid sequence and tertiary protein structure due to altered splicing sites or nonsense mutations. In contrast, point mutations, resulting in a complete defect of the enzymatic activity, are relatively rare [Geller et al, 1997;Auchus, 2001;Van Den Akker et al, 2002;Brooke et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

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Rare Missense P450c17 (CYP17A1) Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness' despite Adequate Estradiol Substitution

Athanasoulia

Auer

Riepe

et al. 2013

Sex Dev

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17-Alpha-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive disorder resulting from mutations in the CYP17A1 gene, leading to impaired adrenal and gonadal steroidogenesis. We report for the first time a patient with a missense mutation at codon 96 (R96Q) of the CYP17A1 gene causing a 46,XY disorder of sexual development (DSD) that additionally showed lack of breast development despite highly dosed estradiol replacement treatment. This phenomenon could be attributed to irreversible breast tissue alterations following high serum progesterone levels.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rare Missense P450c17 (CYP17A1) Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness' despite Adequate Estradiol Substitution

Athanasoulia

Auer

Riepe

et al. 2013

Sex Dev

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“…Structural modeling suggests that R96 lies within the flanking strand 2 of b-sheet 1, and the guanidine group of R96 appears to form hydrogen bonds with carbonyl groups of residues A113 and F114 (18). Removal of this positively charged group, which occurs in p.R96W mutation, appears to instabilize the protein by disrupting this interaction between the two domains, leading to complete enzyme inactivation (3).The severity of clinical disease tends to be milder with mutations that retain a partial catalytic activity (7,19), but the age of onset of hypertension, the degree of hypokalemia, and aldosterone production rate appear to vary, even among patients with the same CYP17 mutations (10,15).…”

Section: Discussionmentioning

confidence: 99%

Combined 17α-hydroxylase/17,20-lyase deficiency due to p.R96W mutation in the CYP17 gene in a Brazilian patient

Costenaro

Rodrigues

Kater

et al. 2010

Arq Bras Endocrinol Metab

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SUMMARYCongenital adrenal hyperplasia (CAH) resulting from 17α-hydroxylase/17,20-lyase deficiency is a rare autosomal recessive disease and the second most common form of CAH in Brazil. We describe the case of a Brazilian patient with CYP17 deficiency (17α-hydroxylase/17,20-lyase deficiency) caused by a homozygous p.R96W mutation on exon 1 of the CYP17 gene, an unusual genotype in Brazilian patients with this form of CAH. The patient, raised as a normal female, sought medical care for lack of pubertal signs and primary amenorrhea at the age of 16 years. At evaluation, the presence of a 46,XY karyotype, hypertension and hypokalemia were observed. We emphasize the recognition of CYP17 deficiency in the differential diagnosis of cases of hypergonadotrophic hypogonadism and hypertension in young patients who need specific treatment for both situations. Arq Bras Endocrinol Metab. 2010;54(8):744-8 SUMÁRIO A hiperplasia adrenal congênita (HAC), em razão da deficiência de 17α-hidroxilase/17,20-liase, é uma doença autossômica recessiva rara e a segunda causa mais comum de HAC no Brasil. Descrevemos o caso de um paciente brasileiro portador da deficiência 17α-hidroxilase/17,20-liase (CYP17) em homozigose para a mutação p.R96W no éxon 1 do gene da CYP17A1, uma mutação incomum entre os casos brasileiros descritos com essa forma de HAC. Esse paciente, criado como um indivíduo normal do sexo feminino, procurou atendimento por ausência de sinais puberais e amenorreia primária aos 16 anos de idade. Durante a avaliação, constataram-se um cariótipo 46,XY e a presença de hipertensão e hipocalemia. Enfatizamos o reconhecimento da deficiência da CYP17 dentre os possíveis diagnósticos em um paciente jovem com hipogonadismo hipergonadotrófico e hipertensão, os quais necessitam de tratamento particularizado para ambas as situações. Arq Bras Endocrinol Metab. 2010;54(8):744-8

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A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development

Pyle

Nathanson

2017

American J of Med Genetics Pt C

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Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist.

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A Novel Point Mutation in P450c17 (CYP17) Causing Combined 17α-Hydroxylase/17,20-Lyase Deficiency

Cited by 40 publications

References 21 publications

Rare Missense P450c17 <b><i>(CYP17A1)</i></b> Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness' despite Adequate Estradiol Substitution

Rare Missense P450c17 <b><i>(CYP17A1)</i></b> Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness' despite Adequate Estradiol Substitution

Combined 17α-hydroxylase/17,20-lyase deficiency due to p.R96W mutation in the CYP17 gene in a Brazilian patient

A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development

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