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

基因型 表型 遗传学 相关性 明星(博弈论) 生物 内科学 基因型-表型区分 医学 基因 天体物理学 物理 数学 几何学
作者
Emre Murat Altınkılıç,Philipp Augsburger,Amit V. Pandey,Christa Flueck
出处
期刊:Journal of Endocrinology [Bioscientifica]
卷期号:262 (3)
标识
DOI:10.1530/joe-24-0078
摘要

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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