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Using the Kompetitive Allele Specific PCR method, we detected this mutation in 2,151 sheep from six different breeds. Association analysis revealed that this mutation affects the growth traits of Luxi Blackhead sheep, and the individuals with AA (K100) genotype exhibited superior growth performance compared to the GG (E100) genotype. Additionally, whole-genome sequencing data from 49 sheep breeds, totaling 968 individuals, showed a higher mutation frequency of this variant in some large-sized sheep breeds. Functional studies demonstrated that the E100K mutation does not affect protein localization or transport but reduces surface and total protein expression. The mutated receptor exhibited decreased basal activity and reduced binding efficiency with agonists (\u03b1-MSH and \u03b2-MSH), resulting in a partial loss of function. Transcriptomic analysis indicated that this mutation affects downstream pathways, including osteoclast differentiation and the MAPK signaling pathway, which may influence growth regulation associated with the E100K mutation. Collectively, these findings underscore the substantial role of the partial loss-of-function MC4R E100K mutation in regulating growth traits in sheep.<\/jats:p>","DOI":"10.1093\/jas\/skag011","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T12:23:29Z","timestamp":1768825409000},"source":"Crossref","is-referenced-by-count":0,"title":["A conserved functional missense SNP (E100K) in sheep\n                    <i>MC4R<\/i>\n                    gene leading to functional loss and impacting the growth traits"],"prefix":"10.1093","volume":"104","author":[{"given":"Yuta","family":"Yang","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peiyao","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taotao","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangding","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8584-4100","authenticated-orcid":false,"given":"Ran","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingfeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Aoqun Animal Husbandry Co., Ltd, Tianjin, 301606,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanying","family":"Pan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianyong","family":"Lan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi, 712100,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"2026022801265065400_skag011-B1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.theriogenology.2022.06.020","article-title":"Newly reported 90-bp deletion within the ovine BMPRIB gene: Does it widely distribute, link to the famous FecB (p.Q249R) mutation, and affect litter size?","volume":"189","author":"Akhatayeva","year":"2022","journal-title":"Theriogenology"},{"issue":"1-2","key":"2026022801265065400_skag011-B2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.diff.2016.02.005","article-title":"Key transcription factors in the differentiation of mesenchymal stem cells","volume":"92","author":"Almalki","year":"2016","journal-title":"Differentiation"},{"issue":"3","key":"2026022801265065400_skag011-B3","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1002\/vms3.421","article-title":"Two co-inherited novel SNPs in the MC4R gene related to live body weight and hormonal assays in Awassi and Arabi sheep breeds of Iraq","volume":"7","author":"Al-Thuwaini","year":"2021","journal-title":"Vet. 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