A New Compound Heterozygous Mutation In CYP17A1 Gene Causes 17α-hydroxylase Deficiency And Pedigree Study

Background:17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia(CAH), characterized by hypertension and sexual infantilism and caused by loss of function mutations in CYP17A1.Human CYP17A1 gene is located on chromosome 10q24.3. It consists of eight exons encoding 508 amino acids. Until now, more than 90 mutations have been found in the Human Gene Mutation Database(HGMD)(http://www.hgmd.org/). The resereh of 17a-hydroxylase defieieney mainly foeused on two aspects: 1. Sequenced the CYPI7A1 gene to identify the mutation, then constructed a recombinant containing the mutation to identify the effect of mutation to the function of P450c17. 2. Built a three-dimensional computer modeling for P450c17 enzyme to predice the effect of mutation to the function of P450c17.Objective:Our purpose of this research is to sequenced CYPI7A1 gene of a case in our hospital with 17α-hydroxylase/17,20-lyase deficiency and her family.3. MateriaIs and Methods:Proband: a 15 years old phenotypic female with karyotype of 46,XY, the first affiliated hospital of zhengzhou university in 2013. She presented with primary hypertension、genital malformations and primary gonadal failure. The biochemical features of the patient is elevated levels of plasma adrenocorticotropic hormone, FSH 、 LH, and reduced testosterone and dehydroepiandrosterone sulfate(DHEA-S).All coding exons and flanking intronic sequences of CYP17A1 of the proband and her parents、grandparents and material grandparents were directly sequenced using genomic DNA. At the end, sepuencing results were compared with the established human CYPI7A1 sequence(Gene Bank ID:1586).Result:1.Synonymous mutation: ① codon 46 from CAT to CAC, H46 H in extron 1; ② codon 65 from TCT to TCG, S65 S in extron 1. 2.Nonsense mutation: base substitution of condon 139 in the non-coding region of extron 1(T→C). 3.Missense mutation: in extron 4,the substitution of 41(T→A), cause 236 amion acid from Val to Asp, the proband and her mother、maternal grandmother were heterozgous mutations, but there were normal in her father 、 grandparents and maternal grandfather.4. Deletion-insertion combined mutation: a deletion-insertion combined mutation(TAC-->AA) at codon 329 in exon 6, Y329 K,418X. the proband and her father、grandfather were heterozgous mutations, but there were normal in her mother、grandmother and maternal grandparents.Conclusion: We analyzed the CYP17A1 gene features in the proband and her family, a novol compound heterozyous mutation were found: missense mutation V236 D in extron 4, which has not been reported before, and a deletion-insertion combined mutation(Y329K,418X), which is prevalent in China.