Clinical spectrum of human STAR variants and their genotype–phenotype correlation

in Journal of Endocrinology
Authors:
Emre Murat Altinkilic Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland

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Philipp Augsburger Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland

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Amit V Pandey Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland

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Christa E Flück Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland

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https://orcid.org/0000-0002-4568-5504

Correspondence should be addressed to C Flueck: christa.flueck@unibe.ch

This paper forms part of a special collection marking 30 Years Since the Identification and Characterization of the StAR Protein. The guest editors for this collection were Professor Doug Stocco, Professor Barbara Clark and Professor Ernesto Podesta.

DOI:
https://doi.org/10.1530/JOE-24-0078
Volume/Issue:
Volume 262: Issue 3
Article Type:
Review Article
Article ID:
e240078
Online Publication Date:
18 Jul 2024
Copyright:
© the author(s) 2024
Restricted access
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Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype–phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2024
Article ID:
e240078
Article Type:
Review Article
Received Date:
04 Mar 2024
Accepted Date:
24 Jun 2024
Print Publication Date:
01 Sep 2024
Online Publication Date:
18 Jul 2024
Keywords:
disorders of sex development; genetic variants; genotype–phenotype correlation; primary adrenal insufficiency; STAR; steroidogenic acute regulatory protein

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