title: Loss of cytochrome P450 17A1 protein expression in a 17alpha-hydroxylase/17,20-lyase-deficient 46,XY female caused by two novel mutations in the CYP17A1 gene.
abstract: 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.
authors.affiliation: Department of Human Genetics, Hospital General de México-Facultad de Medicina Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Nayelli
authors.initials: N
authors.lastname: Nájera
authors.forename: Nayely
authors.initials: N
authors.lastname: Garibay
authors.forename: Yadira
authors.initials: Y
authors.lastname: Pastrana
authors.forename: Icela
authors.initials: I
authors.lastname: Palma
authors.forename: Yolanda-Rocio
authors.initials: YR
authors.lastname: Peña
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez
authors.forename: Ninel
authors.initials: N
authors.lastname: Coyote
authors.forename: Alberto
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Susana
authors.initials: S
authors.lastname: Kofman-Alfaro
authors.forename: Gloria
authors.initials: G
authors.lastname: Queipo
mesh_terms: D000052:Acanthosis Nigricans / Q000175:diagnosis; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000201:enzymology*; D000324:Adrenocorticotropic Hormone; D001483:Base Sequence; D004247:DNA / Q000097:blood / Q000737:chemistry; D004958:Estradiol / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood; D006059:Gonadal Dysgenesis / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009154:Mutation; D010641:Phenotype; D011627:Puberty; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D013737:Testis / Q000201:enzymology; D013739:Testosterone / Q000097:blood
chemical_list: D013739:Testosterone; D004958:Estradiol; D000324:Adrenocorticotropic Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D004247:DNA; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D006854:Hydrocortisone