The palate is a structure separating the oral and nasal cavities and its integrity is essential for feeding and breathing. The total or partial opening of the palate is called a cleft palate and is a common malformation in mammals with environmental or hereditary aetiologies. Generally, it compromises life expectancy in the absence of surgical repair. A new form of non-syndromic cleft palate arose recently in Limousine cattle, with animals referred to the French National Observatory of Bovine Abnormalities since 2012. Since the number of affected animals has increased steadily, this study was undertaken to identify the cause of this disease. Based on pedigree analysis, occurrence of cleft palate in Limousine cattle was concordant with an autosomal recessive mode of inheritance. Genotyping of 16 affected animals and homozygosity mapping led to the identification of a single disease-associated haplotype on Bos taurus chromosome (BTA)19. The genome of two affected animals was sequenced, and their sequences were compared to the ARS-UCD1.2 reference genome to identify variants. The likely causal variants were compared to the variant database of the 1000 bull genome project and two fully linked mutations in exon 24 of the MYH3 (myosin heavy chain) gene were detected: a 1-bp non-synonymous substitution (BTA19:g.29609623A>G) and a 11-bp frameshift deletion (BTA19:g.29609605-29609615del). These two mutations were specific to the Limousine breed, with an estimated allele frequency of 2.4% and are predicted to be deleterious. The frameshift leads to a premature termination codon. Accordingly, mRNA and protein analyses in muscles from wild-type and affected animals revealed a decrease in MYH3 expression in affected animals, probably due to mRNA decay, as well as an absence of the MYH3 protein in these animals. MYH3 is mostly expressed in muscles, including craniofacial muscles, during embryogenesis, and its absence may impair palate formation. We describe a new form of hereditary cleft palate in Limousine cattle. We identified two fully linked and deleterious mutations, ultimately leading to the loss-of-function of the MYH3 protein. The mutations were included on the Illumina EuroG10k v8 and EuroGMD v1 SNP chips and are used to set up a reliable eradication strategy in the French Limousine breed.

中文翻译：

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MYH3 基因突变导致豪华轿车隐性腭裂

上颚是分隔口腔和鼻腔的结构，其完整性对于进食和呼吸至关重要。腭的全部或部分开口称为腭裂，是哺乳动物中常见的畸形，具有环境或遗传性病因。通常，在没有手术修复的情况下，它会影响预期寿命。最近在豪华轿车中出现了一种新形式的非综合征性腭裂，自 2012 年以来，这些动物被转诊至法国国家牛异常观察站。由于受影响动物的数量稳步增加，因此开展了这项研究以确定这种疾病的原因. 基于系谱分析，豪华轿车腭裂的发生与常染色体隐性遗传模式一致。对 16 只受影响动物的基因分型和纯合性作图导致在金牛座染色体 (BTA)19 上鉴定出单一的疾病相关单倍型。对两只受影响动物的基因组进行测序，并将它们的序列与 ARS-UCD1.2 参考基因组进行比较以识别变异。将可能的因果变异与 1000 牛基因组计划的变异数据库进行比较，并在 MYH3（肌球蛋白重链）基因的外显子 24 中检测到两个完全连锁的突变：1-bp 非同义替换（BTA19:g.29609623A >G) 和 11-bp 移码缺失 (BTA19:g.29609605-29609615del)。这两个突变是 Limousine 品种特有的，估计等位基因频率为 2.4%，预计是有害的。移码导致过早终止密码子。因此，野生型和受影响动物肌肉中的 mRNA 和蛋白质分析显示，受影响动物的 MYH3 表达减少，可能是由于 mRNA 衰变，以及这些动物中缺乏 MYH3 蛋白。MYH3 在胚胎发生过程中主要在肌肉中表达，包括颅面肌，它的缺失可能会损害上颚的形成。我们描述了豪华轿车牛的一种新形式的遗传性腭裂。我们确定了两个完全相关的有害突变，最终导致 MYH3 蛋白功能丧失。这些突变包含在 Illumina EuroG10k v8 和 EuroGMD v1 SNP 芯片上，用于在法国豪华轿车品种中建立可靠的根除策略。以及这些动物中缺乏 MYH3 蛋白。MYH3 在胚胎发生过程中主要在肌肉中表达，包括颅面肌，它的缺失可能会损害上颚的形成。我们描述了豪华轿车牛的一种新形式的遗传性腭裂。我们确定了两个完全相关的有害突变，最终导致 MYH3 蛋白功能丧失。这些突变包含在 Illumina EuroG10k v8 和 EuroGMD v1 SNP 芯片上，用于在法国豪华轿车品种中建立可靠的根除策略。以及这些动物中缺乏 MYH3 蛋白。MYH3 在胚胎发生过程中主要在肌肉中表达，包括颅面肌，它的缺失可能会损害上颚的形成。我们描述了豪华轿车牛的一种新形式的遗传性腭裂。我们确定了两个完全相关的有害突变，最终导致 MYH3 蛋白功能丧失。这些突变包含在 Illumina EuroG10k v8 和 EuroGMD v1 SNP 芯片上，用于在法国豪华轿车品种中建立可靠的根除策略。我们确定了两个完全相关的有害突变，最终导致 MYH3 蛋白功能丧失。这些突变包含在 Illumina EuroG10k v8 和 EuroGMD v1 SNP 芯片上，用于在法国豪华轿车品种中建立可靠的根除策略。我们确定了两个完全相关的有害突变，最终导致 MYH3 蛋白功能丧失。这些突变包含在 Illumina EuroG10k v8 和 EuroGMD v1 SNP 芯片上，用于在法国豪华轿车品种中建立可靠的根除策略。