Combined 17 alpha-hydroxylase/17,20-lyase deficiency due to a homozygous 25 BP duplication (NT 4157-4181) at exon 5 in the CYP17 resulting in a premature stop codon predicted by molecular modeling

Abstract

Combined 17alpha-hydroxylase/17,20-lyase defi ciency is a rare, autosomal recessive form of congenital adrenal hyperplasia characterized by the coexistence of hypertension, caused by the hyperproduction of mineralocorticoid precursors and DSD in males and sexual infantilism in females, due to impaired production of sex hormones. Several CYP17 mutations resulting in 17al-pha-hydroxylase/17,20-lyase defi ciency have been reported previously. In the present study, we described a novel CYP17 mutation in two Brazilian sisters with primary amenorrhea, 46,XY karyotype, high basal levels of progesterone (3.4-4.9 ng/mL) and hypokalemic hypertension born to consanguineous parents. After PCR and automatic sequencing of CYP17 coding region, 25 bp duplication at exon 5 was found in the patients. This duplication started at codon 318 resulting in a premature stop codon at position 320 resulting in an ineffective and truncated protein and in accordance with the molecular modeling of P450c17. Therefore we expanded the repertoire of CYP17 mutations describing the largest duplication found in this gene in both sisters, with a clinical phenotype of combined 17alpha-hydroxylase/17,20-lyase defi ciency and emphasizes the importance of the P450c 17 molecular modeling to predict the functional effect of these mutations. A defi ciência combinada de 17 alfa-hidroxilase/17,20 liase é uma doença rara, de herança autossômica recessiva, causa de hiperplasia adrenal congênita caracterizada pela presença de hipertensão resultante do acúmulo de precursores mineralocorticóides, distúrbio da diferenciação sexual em homens e infantilismo sexual em mulheres devido à falha na produção de esteróides sexuais. Várias mutações no gene CYP17 resultando em defi ciência de 17 alfa-hidroxilase/17,20-liase têm sido descritas. No presente estudo, descrevemos uma nova mutação no CYP17 em duas irmãs, nascidas de pais consangüíneos, com quadro de amenorréia primária, cariótipo 46,XY, dosagens basais elevadas de progesterona (3,4-4,9 ng/mL) e hipertensão hipocalêmica. Após PCR e seqüenciamento automático da região codifi cadora do CYP17, uma duplicação de 25 pb no exon 5 foi identifi cada nas pacientes. Esta duplicação inicia-se no códon 318 resultando em parada prematura de leitura no códon 320 gerando uma proteína truncada e inativa conforme predito pela modelagem molecular do P450c17. Com este achado, ampliamos o repertório de mutações do CYP17 descrevendo a maior duplicação descrita até então neste gene em duas irmãs com fenótipo de deficiência combinada de 17 alfa-hidroxilase/17,20-liase e enfatizamos a importância da modelagem molecular do P450c 17 em predizer o efeito funcional destas mutações.

Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil

“…Most reports describe isolated cases in consanguineous families (2), and approximately 50 different mutations in CYP17A1 have been described, although some are more common and reoccur in certain ethnic groups. Most mutations have been seen to cause combined 17α-hydroxylase/17,20-lyase enzyme deficiency (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

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

“…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). Patients with partial 17α-hydroxylase deficiency can have ambiguous genitalia at birth (7,15,19).…”

“…Previously, 30 Brazilian subjects with 17α-hvdroxylase deficiency from 24 kindred were reported and seven CYP17 gene mutations were reported in this sample (9). Recently, a new mutation of 25 bp duplication at exon 5 of CYP17 was described in two Brazilian sisters (46,XY kariotype), with the classical clinical presentation of this enzymatic defect and with P450c17 molecular modeling predicting the loss of both enzymatic activities of this protein (10).…”

Intrauterine sexual differentiation: biosyntesis and action of sexual steroid hormones

“…Other anomalies of sexual differentiation are sexual infantilism in women, syndrome of polycystic ovary (Costanzo 1998;Nóbrega et al 2004;Martin et al 2008;Costenaro et al 2010;Kalfa et al 2010) and androgen insensitivity from mutations in the genes of these receptors that generate XY individuals with female external genitalia at birth (Domenice et al 2002).…”