A compound heterozygous mutation in the CYP17 (17α-hydroxylase/17,20-lyase) gene in a Chinese subject with congenital adrenal hyperplasia

Won, Gin-Sing; Chiu, C. J.; Tso, Yi-Chu; Jenq, Shwu-Fen; Cheng, Pi-Sung; Jap, Tjin-Shing

doi:10.1016/j.metabol.2006.11.009

Cited by 12 publications

(11 citation statements)

References 20 publications

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“…The same effects are observed in other P450 enzyme mutations, such as the CYP21A2 gene mutations that are the most frequent cause of CAH. Mutations within the ExxR motif lead to complete loss of activity, supporting the fact that small C-terminal alterations can destroy most or all protein function [10,11,[18][19][20][21]. The clinical features and the absence of immunodetectable enzyme support the loss of enzyme activity.…”

Section: Discussionmentioning

confidence: 85%

“…The serpentine chain of residues that follows tends to unwind the K helix, and hydrogen bonding between the adjacent E and R residues in this motif stabilizes this structure and helps to form the redox partner binding site [10][11][12]. Thus, any mutations in this critical region or near this domain weaken hydrogen bonding within the ExxR motif and completely abolish enzymatic activity, as has been previously reported for the R362C mutation [10][11][12]. The same effects are observed in other P450 enzyme mutations, such as the CYP21A2 gene mutations that are the most frequent cause of CAH.…”

Section: Discussionmentioning

confidence: 99%

“…However, even among patients harboring mutations that completely inactivate the enzyme, the age of onset of hypertension, the degree of hypokalemia, and aldosterone production rate may vary [9]. Recent studies have attempted to establish a correlation between genotype and phenotype; however, it is clear that more molecular data are required to fully understand how this complex enzyme functions [10][11][12]. There are currently no reports of CAH attributable to complete 17OHD in the Mexican population.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Cytochrome P450 17A1 Protein Expression in a 17α-Hydroxylase/17,20-Lyase-Deficient 46,XY Female Caused by Two Novel Mutations in the CYP17A1 Gene

et al. 2009

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17alpha-Hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the CYP17A1 gene. This condition shows considerable clinical and biochemical variation. Molecular characterization of novel mutations in the CYP17A1 gene and detailed study of their structural, enzymatic, and clinical consequences are required to fully understand enzyme behavior. Here, we present the first molecular characterization of two novel mutations in CYP17A1 in a 15-year-old female Mexican mestizo 46,XY female with primary amenorrhea and lack of pubertal development and severe hypertension that manifested only after surgery. A complete clinical and biochemical evaluation was compatible with 17OHD. Structural anomalies in the CYP17A1 gene were discovered by direct automated sequencing, which revealed a novel compound heterozygous K110X/R362H mutation that leads to a complete lack of enzyme activity. Immunohistochemical analyses performed to determine protein expression and localization showed that cytochrome P450 17A1 was completely absent in the patient's testicular tissue. Studies of novel mutations, such as those described here, provide important information that allows us to better understand the effect of a given mutation on enzyme function and to observe the impact of the mutation on clinical phenotype.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of Cytochrome P450 17A1 Protein Expression in a 17α-Hydroxylase/17,20-Lyase-Deficient 46,XY Female Caused by Two Novel Mutations in the CYP17A1 Gene

et al. 2009

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“…The phenotype of affected individuals varies according to the severity of the mutation; this includes undescended testes, infertility, pseudohermaphroditism, and ambiguous genitalia. Mutations have been identified in the genes encoding the LH receptor (LHCGR) [22], INSL3 [23][24][25], and enzymes involved in testosterone biosynthesis [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. Gene mutations affecting transcription factors associated with disruption of Leydig cell development and/or function in humans have also been described (see below).…”

Section: Origin and Function Of Leydig Cellsmentioning

confidence: 99%

Molecular regulation of steroidogenesis in endocrine Leydig cells

Tremblay

2015

Steroids

146

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“…It is caused by a mutation in the CYP17A1 gene. To date, more than 200 cases of 17OHD and more than 50 different mutations have been reported all over the world, most of which lead to a clinical outcome of complete 17OHD (1,2) . Here we report a Wei Wang and Fang-Qi Gong contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Rare hypertension as a result of 17α-hydroxylase deficiency

Wang

Fu²,

Gong³

et al. 2011

Journal of Pediatric Endocrinology and Metabolism

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Purpose : To investigate CYP17A1 gene mutations in Chinese patients with 17 α -hydroxylase defi ciency. Methods : Clinical data were retrospectively analyzed. CYP17A1 mutations were detected in two cases with 17 α -hydroxylase defi ciency. Genomic DNA was isolated from blood samples and eight primers pairs were used to amplify eight exons and exon -intron boundaries of the CYP17A1 gene. The amplifi ed PCR products were purifi ed by agarose gel electrophoresis and then directly sequenced. Sequencing results were compared to the established human CYP17A1 sequence. Results : Two compound mutations were identifi ed: TAC → AA at codons 436 -438 on exon 6, causing the amino acid missense mutation Y329K/418X; and deletion of the 9-bp sequence GACTCTTTC at codons 487 -489 on exon 8, causing deletion of three amino acids (Asp-Ser-Phe). Conclusion : D487_F489del and Y329K, 418X CYP17A1 mutations were identifi ed in our two patients. A literature review revealed that the main CYP17A1 mutations in the Chinese population are missense and splicing defects, and exons 8 and 6 are most frequently involved.

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A compound heterozygous mutation in the CYP17 (17α-hydroxylase/17,20-lyase) gene in a Chinese subject with congenital adrenal hyperplasia

Cited by 12 publications

References 20 publications

Loss of Cytochrome P450 17A1 Protein Expression in a 17α-Hydroxylase/17,20-Lyase-Deficient 46,XY Female Caused by Two Novel Mutations in the CYP17A1 Gene

Loss of Cytochrome P450 17A1 Protein Expression in a 17α-Hydroxylase/17,20-Lyase-Deficient 46,XY Female Caused by Two Novel Mutations in the CYP17A1 Gene

Molecular regulation of steroidogenesis in endocrine Leydig cells

Rare hypertension as a result of 17α-hydroxylase deficiency

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