FRRS1L基因变异和高铁血红素过载导致兰坪乌骨羊色素沉着过度和全身性铁过载。

FRRS1L variants and ferriheme overload drive hyperpigmentation and systemic Iron overload in lanping black bone sheep.

作者信息

Han Deping, Zhang Yuanyuan, Deng Weidong, Yang Xue, Chen Jianfei, Hua Guoying, Darwish Hesham Y A, Mao Huaming, Gou Xiao, Wang Jiankui, Cui Kai, Ma Yuhao, Tai Yurong, Dong Xianggui, Yao Yanzhu, Yang Zu, Cao Suying, Yu Zhengquan, Liu Wansheng, Deng Xuemei

机构信息

Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing, 100193, China.

Laboratory of Advanced Agricultural Sciences in Weifang, Peking University Institute of Advanced Agricultural Sciences, Weifang City, 261325, Shandong, China.

出版信息

Cell Biosci. 2025 Jun 24;15(1):87. doi: 10.1186/s13578-025-01426-6.

DOI:10.1186/s13578-025-01426-6

PMID:40556005

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12188663/

Abstract

BACKGROUND

Hemoglobin metabolism disorder can result in systemic iron overload, leading to pigmentation in multiple organs. Although these disorders are often of genetic origin, the specific genes and mechanisms remain incompletely understood. Lanping black bone sheep (LP–BBS), a unique population from the high altitudes along the Hengduan Mountains in Yunnan province, exhibits hyperpigmentation in multiple tissues. Investigating the genetic and environmental factors underlying this phenotype provides a natural model to better understand hemoglobin metabolism disorder.

RESULTS

LP-BBS were found to exhibit increased red blood cell counts, elevated hemoglobin levels, and systemic iron overload, evidenced by hyperpigmentation in various tissues. Histological and molecular analyses revealed that hyperpigmentation is driven by ferriheme overload, an inheritable quantitative trait influenced by both genetic variation and environmental factors. Genome-wide association studies identified as a candidate gene, with significant mutations in its 3′-untranslated region (3′-UTR) reducing expression. Functional assays demonstrated that insufficient expression promotes ferriheme accumulation in reticuloendothelial cells and macrophages, as confirmed in vitro using knockdown models. Ferriheme overload was associated with oxidative stress and systemic inflammation, causing pathological damage to critical organs such as the kidney, liver, and uterus.

CONCLUSION

This study identifies as a key contributor to ferriheme overload through aberrant hemoglobin metabolism in LP–BBS. These findings offer new insights into the genetic basis and pathological mechanisms of iron overload disorders, providing a potential target for therapeutic intervention. Moreover, LP–BBS serves as a valuable natural model for studying hematogenous pigment disorders and their interplay with environmental factors.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s13578-025-01426-6.

摘要

背景

血红蛋白代谢紊乱可导致全身铁过载，进而引发多个器官的色素沉着。尽管这些紊乱通常源于遗传，但具体基因和机制仍未完全明确。兰坪乌骨羊（LP - BBS）是来自云南省横断山脉高海拔地区的独特种群，在多个组织中表现出色素沉着过度。研究该表型背后的遗传和环境因素，为更好地理解血红蛋白代谢紊乱提供了一个自然模型。

结果

发现LP - BBS的红细胞计数增加、血红蛋白水平升高以及全身铁过载，各种组织的色素沉着过度即为证据。组织学和分子分析表明，色素沉着过度是由高铁血红素过载驱动的，这是一种受遗传变异和环境因素影响的可遗传数量性状。全基因组关联研究确定[基因名称]为候选基因，其3′非翻译区（3′-UTR）的显著突变降低了[基因名称]的表达。功能试验表明，[基因名称]表达不足会促进高铁血红素在网状内皮细胞和巨噬细胞中的积累，这在使用[基因名称]敲低模型的体外实验中得到了证实。高铁血红素过载与氧化应激和全身炎症相关，对肾脏、肝脏和子宫等关键器官造成病理损害。