The Functional Characterization Study Of CYP21A2 Gene Mutation Causing 21-hydroxylase Deficiency In One Pedigree

BackgroundCongenital adrenal hyperplasia (CAH) is a human autosomal recessive hereditary disease,21-hydroxylase deficiency (21-OHD) is the most common type, which accounts for more than 90-95%.21-OHD is the most common inborn error of metabolism, which has a wide variety of clinical forms. Ranging from classical, embracing the SV and salt-wasting (SW), to the nonclassical form. Infertile synthesis of cortisol, with or without lacking of aldosterone, leads to chronic stimulation of the adrenal cortex by adrenocorticotropic hormone (ACTH). As a result, overproduction of cerrtain cortisol precursors are forced into the androgen biosynthetic pathway, leading to the signs and symptoms of androgen excess presented in this disorder. Girls with classical CAH are most born with ambiguous genitalia resulted from the exposure to high body adrenal androgen levels from the 7th week of pregnancy. Patients with a simultaneous defect in aldosterone biosynthesis are in life-threatening conditions which often appear at 1-4 weeks of age in girls and boys. The moderate enzyme deficiency that brings about NCCAH is characterized by signs of hyperandrogenism such as hirsutism, oligomenorrhea, amenorrhea, polycystic ovaries,acne and infertility.P450c21 is the affected enzyme, which is encoded by the CYP21A2 gene. P450c21 is located on chromosome 6p21.3 next to a pseudogene named CYP21A1P. These two genes have 98% nucleotide sequence identity. Because of high homology between these two genes, most of the mutations resulted in disease described are likely to be the ending of non-homologous reorganization or gene conversion events. What’s more, about 130 rare point mutations that occur independently of the pseudogene and they were found specific to a race or a single family, have been described so far. Our research results help to further clarify the relationship between genotype and phenotype, providing the update perspective for P450c21 function study. These results provide important information for patient counseling and doctor and offer the foundation of prenatal diagnosis, improving the conversion rate of the disease.ObjectiveIn the study, we aimed to research the clinical manifestations and genetic characteristics of one Chinese pedigrees to summarise the deeper and comprehensive development in 21-OHD genetics, diagnosis, and management.Subjects and MethodsOne two-generation family with 21-OHD was identified and screened for mutations in the CYP21A2 gene. Correlations genotype and phenotype were analysed.ResultsThe clinical manifestations of the proband were as follows:the excessive androgen secretion, hairy, acne, prominentia laryngea, breast dysplasia, the clitoris. CYP21A2 gene sequencing results showed that the proband was compound heterozygote. and the mutations had not been reported at home and abroad. These mutations are missense point mutations c.1024 c> T (p. Arg342Trp) in the exon 8 and heterozygous mutations in the exon 1, exon 3, exon 4 exon6 and exon 7. We hypothesized that these new mutations seriously caused the destruction of protein structure and function. Half a year time, curative effect of proband after taking dexamethasone is satisfactory.ConclusionThe new discovered CYP21A2 gene mutations in our study were the causes of 21-OHD, laying a foundation for further research of the gene functions and offerring more important information to patients and medical persons, which can help to improve the conversion rate of the disease.