A Novel Splice Site Mutation in the StAR Gene Causes Congenital Adrenal Hyperplasia in a 46,XX Patient

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 358-380-Steroid Hormone Biosynthesis & Metabolism
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-359
Núria Camats*1, Amit V Pandey1, Mónica Fernández-Cancio2, Juan Manuel Fernández3, Sameer Udhane1, Primus E Mullis1, Antonio Carrascosa2, Laura Audí2 and Christa E Flück1
1University Children's Hospital Bern, Bern, Switzerland, 2Hospital Universitari Vall d'Hebrón, Barcelona, Spain, 3Hospital Clínico, Granada, Spain

Steroid hormone biosynthesis produces mineralocorticoid, glucocorticoid and sex steroids from cholesterol in the adrenal glands and sex steroids in the gonads. The steroidogenic acute regulatory protein (StAR) is crucial for this pathway because it transports cholesterol from the cytosol to the inner membrane of the mitochondria. A loss of StAR function can cause congenital adrenal hyperplasia (CAH), characterized by the impaired synthesis of all adrenal and gonadal steroid hormones causing adrenal insufficiency and female external genitalia irrespective of genetic sex in newborn patients.


A newborn girl (12 h, consanguineous parents) was admitted to the Intensive Care Unit because of a choking crisis with hypotonia. She had normal external female genitalia without hyperpigmentation, and presented mild dehydration, hyponatremia, hyperkalemia and hypoglycemia, suggesting possible CAH. Biochemistry revealed a decrease in plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone and an increase in ACTH and plasma renin activity consistent with the diagnosis of primary adrenal insufficiency. Adrenal capsule antibodies were negative and very-long-chain fatty acids normal. NMR showed normal adrenal glands and cytogenetics revealed a normal a 46,XX karyotype. She was normalized by fluid therapy with hydrocortisone, 9a-fludrocortisone and NaCl.

Methods and Results

Genetic studies were performed, involving the analysis of the MC2R, MRAP, CYP11A1 and StAR genes. StAR gene presented a novel homozygous mutation in the 3’ acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A).

We hypothesized that the mutation would produce an aberrant splicing of the mRNA. To test this, we performed a minigene in vitro study. We constructed a wild-type (WT) and a mutant StAR minigene including a 4-to-6-exon sequence in an expression vector, which were transfected in COS-1 cells. The splicing was assessed by RT-PCR for StAR cDNAs on extracted total RNA.

The study showed that the mutant StAR minigene was processed to a shorter cDNA fragment than the WT and sequencing revealed that the mutant contained the full sequence of exons 4 and 6, but exon 5 in-between was completely missing. Biocomputational studies revealed that exon 5 is crucial for the StAR-cholesterol interaction.


StAR c.466-1A skips exon 5, which is essential for the function of StAR. This splicing mutation is a loss-of-function mutation that causes the phenotype of our patient.

Nothing to Disclose: NC, AVP, MF, JMF, SU, PEM, AC, LA, CEF

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: N.C. is supported by ESPE Research Fellowship, sponsored by Novo Nordisk A/S.