TY - JOUR
T1 - 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
AU - Nájera, Nayelli
AU - Garibay, Nayely
AU - Pastrana, Yadira
AU - Palma, Icela
AU - Peña, Yolanda Rocio
AU - Pérez, Javier
AU - Coyote, Ninel
AU - Hidalgo, Alberto
AU - Kofman-Alfaro, Susana
AU - Queipo, Gloria
N1 - Funding Information:
Acknowledgments This work was supported by grants from the Research Division of the Hospital General de México, CONACYT (48017), and the Universidad Nacional Autónoma de México DGAPA (IN225608-3 UNAM)
PY - 2009/12
Y1 - 2009/12
N2 - 17α-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.
AB - 17α-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.
KW - 17α-hydroxylase deficiency
KW - CYP17A1 mutations
KW - Congenital adrenal hyperplasia
KW - XY DSD
UR - http://www.scopus.com/inward/record.url?scp=70449527540&partnerID=8YFLogxK
U2 - 10.1007/s12022-009-9088-9
DO - 10.1007/s12022-009-9088-9
M3 - Artículo
C2 - 19728179
SN - 1046-3976
VL - 20
SP - 249
EP - 255
JO - Endocrine Pathology
JF - Endocrine Pathology
IS - 4
ER -