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Clinical Endocrinology

STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases

Authors

  • Núria Camats,

    1. Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland
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  • Amit V. Pandey,

    1. Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland
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  • Mónica Fernández-Cancio,

    1. Pediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
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  • Juan M. Fernández,

    1. Pediatric Endocrinology Service, Hospital Clínico, Granada, Spain
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  • Ana M. Ortega,

    1. Pediatric Endocrinology Service, Hospital Clínico, Granada, Spain
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  • Sameer Udhane,

    1. Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland
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  • Pilar Andaluz,

    1. Pediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
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  • Laura Audí,

    1. Pediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
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  • Christa E. Flück

    Corresponding author
    1. Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland
    • Correspondence: Christa E. Flück, Pediatric Endocrinology and Diabetology, University Children's Hospital Bern, Freiburgstrasse 15, C845, 3010 Bern, Switzerland. Tel.: +41 31 632 04 99; E-mail: christa.flueck@dkf.unibe.ch

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Summary

Objective

The steroidogenic acute regulatory protein (StAR) transports cholesterol to the mitochondria for steroidogenesis. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH) which is characterized by impaired synthesis of adrenal and gonadal steroids causing adrenal insufficiency, 46,XY disorder of sex development (DSD) and failure of pubertal development. Partial loss of StAR activity may cause adrenal insufficiency only.

Patient

A newborn girl was admitted for mild dehydration, hyponatremia, hyperkalemia and hypoglycaemia and had normal external female genitalia without hyperpigmentation. Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency. Imaging showed normal adrenals, and cytogenetics revealed a 46,XX karyotype. She was treated with fluids, hydrocortisone and fludrocortisone.

Design, Methods and Results

Genetic studies revealed a novel homozygous STAR mutation in the 3′ acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A). To test whether this mutation would affect splicing, we performed a minigene experiment with a plasmid construct containing wild-type or mutant StAR gDNA of exons–introns 4–6 in COS-1 cells. The splicing was assessed on total RNA using RT-PCR for STAR cDNAs. The mutant STAR minigene skipped exon 5 completely and changed the reading frame. Thus, it is predicted to produce an aberrant and shorter protein (p.V156GfsX19). Computational analysis revealed that this mutant protein lacks wild-type exons 5–7 which are essential for StAR-cholesterol interaction.

Conclusions

STAR c.466-1A skips exon 5 and causes a dramatic change in the C-terminal sequence of the protein, which is essential for StAR–cholesterol interaction. This splicing mutation is a loss-of-function mutation explaining the severe phenotype of our patient. Thus far, all reported splicing mutations of STAR cause a severe impairment of protein function and phenotype.

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