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A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17{alpha}-hydroxylase deficiency.

Abstract：

BACKGROUND:17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. OBJECTIVE:A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. METHODS AND RESULTS:Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263G>A) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. CONCLUSION:This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.

journal_name

Eur J Endocrinol

journal_title

European journal of endocrinology

authors

Qiao J,Han B,Liu BL,Liu W,Wu JJ,Pan CM,Jiang H,Gu T,Jiang BR,Zhu H,Lu YL,Wu WL,Chen MD,Song HD

doi

10.1530/EJE-10-0933

subject

Has Abstract

pub_date

2011-04-01 00:00:00

pages

627-33

issue

eissn

0804-4643

issn

1479-683X

pii

EJE-10-0933

journal_volume

164

pub_type

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A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17{alpha}-hydroxylase deficiency.