Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig, Germany
Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig, Germany.
Pharmacol Rev. 2021 Jan;73(1):89-119. doi: 10.1124/pharmrev.120.000011.
There are approximately 800 annotated G protein-coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain- and loss-of-function variants, other aspects, such as biased signaling, -signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches. SIGNIFICANCE STATEMENT: With the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein-coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain- and loss-of-function alterations, additional aspects, such as biased signaling, -signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.
大约有 800 个注释的 G 蛋白偶联受体（GPCR）基因，这些膜受体是人类基因组中最丰富的基因家族成员。除了参与多种生理功能外，作为重要的药物治疗靶点，55 个 GPCR 基因突变导致约 66 种人类遗传性单基因疾病。9 个 GPCR 基因的改变与遗传性双基因疾病有关。除了经典的功能获得和丧失变异外，其他方面，如偏向信号、负向信号、异位表达、GPCR 的等位基因变异、假基因、基因融合和基因剂量，也导致了 GPCR 功能障碍的多样性。然而，改变和 GPCR 参与的范围可能要大得多，因为另外 91 个 GPCR 基因在人类个体中含有纯合或杂合功能丧失突变，而这些个体目前具有未知的表型。本文重点介绍 GPCR 基因突变的复杂性及其功能后果，并讨论由此产生的治疗方法。意义陈述：随着新的转基因和测序技术的出现，与 G 蛋白偶联受体（GPCR）突变体相关的单基因疾病数量显著增加，我们对某些类型突变的功能影响的理解也有了很大的提高。除了经典的功能获得和丧失改变外，还需要阐述偏向信号、负向信号、异位表达、GPCR 的等位基因变异、单亲二倍体、假基因、基因融合和基因剂量等其他方面，以阐明 GPCR 功能障碍和可能的治疗策略。
