由单核苷酸变异引起的LEPR、PCSK1和POMC基因的所有错义变异的功能特征。

IF 2.7 Q3 ENDOCRINOLOGY & METABOLISM

Expert Review of Endocrinology & Metabolism Pub Date : 2023-03-01 DOI:10.1080/17446651.2023.2179985

Bhavik P Shah, Patrick M Sleiman, Jessica Mc Donald, Ida H Moeller, Patrick Kleyn

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引用次数: 1

摘要

目的:由MC4R通路基因功能缺失(LOF)变异引起的罕见的黑素皮质素-4受体(MC4R)通路疾病的临床特征是嗜食和早发性严重肥胖。对LEPR、POMC和PCSK1的单核苷酸变异(snv)进行了12879种可能的外显子错义变异的体外功能表征，以确定这些变异对蛋白质功能的影响。方法:将三个基因的snv瞬时转染细胞系，并根据功能影响对每个变异进行分类。我们通过比较29个先前发表的变异的分类和功能特征来验证三种检测方法。结果:我们的结果与先前发表的病原分类显著相关(r = 0.623;P = 3.03 × 10-4)对snv引起的所有潜在错义变异进行了分析。在通过现有数据库和16061例肥胖患者的测试队列确定的所有观察到的变异中，8.6%的LEPR、63.2%的PCSK1和10.6%的POMC变异表现出LOF，包括目前被归类为不确定意义变异(VUS)的变异。结论:本文提供的功能数据有助于对LEPR、PCSK1和POMC中几种VUS进行重新分类，并突出其在MC4R通路疾病中的作用。

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Functional characterization of all missense variants in LEPR, PCSK1, and POMC genes arising from single-nucleotide variants.

Objective: Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pathway. In vitro functional characterization of 12,879 possible exonic missense variants from single-nucleotide variants (SNVs) of LEPR, POMC, and PCSK1 was performed to determine the impact of these variants on protein function.

Methods: SNVs of the three genes were transiently transfected into cell lines, and each variant was subsequently classified according to functional impact. We validated three assays by comparing classifications against functional characterization of 29 previously published variants.

Results: Our results significantly correlated with previously published pathogenic categories (r = 0.623; P = 3.03 × 10^-4) of all potential missense variants arising from SNVs. Of all observed variants identified through available databases and a tested cohort of 16,061 patients with obesity, 8.6% of LEPR, 63.2% of PCSK1, and 10.6% of POMC variants exhibited LOF, including variants currently classified as a variant of uncertain significance (VUS).

Conclusions: The functional data provided here can assist in the reclassification of several VUS in LEPR, PCSK1, and POMC and highlight their impact in MC4R pathway diseases.

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来源期刊

Expert Review of Endocrinology & Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

4.80

自引率

0.00%

发文量

期刊介绍： Implicated in a plethora of regulatory dysfunctions involving growth and development, metabolism, electrolyte balances and reproduction, endocrine disruption is one of the highest priority research topics in the world. As a result, we are now in a position to better detect, characterize and overcome the damage mediated by adverse interaction with the endocrine system. Expert Review of Endocrinology and Metabolism (ISSN 1744-6651), provides extensive coverage of state-of-the-art research and clinical advancements in the field of endocrine control and metabolism, with a focus on screening, prevention, diagnostics, existing and novel therapeutics, as well as related molecular genetics, pathophysiology and epidemiology.