Jacinto Joana G P, Leuenberger Therese, Hauser Miriam, Häfliger Irene M, Seefried Franz R, Letko Anna, Drögemüller Cord
Clinic for Ruminants, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.
Mol Genet Genomics. 2025 Sep 6;300(1):91. doi: 10.1007/s00438-025-02290-2.
The aim of this study was to investigate three unrelated Simmental calves with atypical white coat color, identify potential genetic causes using a trio-based whole-genome sequencing approach, and assess the prevalence of the identified variants in the breed. Several inherited alleles affecting coat color, ranging from fawn to red spotted and white-headed, have been described in Simmental cattle originating from Switzerland. However, no genetic variant has yet been associated with an almost completely white coat in this breed. Clinical examination revealed different syndromic disorders of white coat color in Simmental in all three cases, and pedigree records indicated recessive inheritance. Filtering for rare protein-changing variants revealed an independent homozygous variant that could be the cause in each case: a likely pathogenic missense variant in TYR (NP_851344.1:p.Pro428Leu) in case 1 with oculocutaneous albinism type 1, a likely pathogenic missense variant in GRID1 (XP_024842694.1:p.Pro489His) in case 2 with short stature-auditory depigmentation syndrome, and a frameshift variant of uncertain significance in RAD54B (NP_001179884.1:p.Ala722_Gly724delinsAsnLeuIlePheCys*) in case 3 with a multisystem depigmentation syndrome. Validation by Sanger sequencing confirmed the variant genotypes, and parental heterozygosity supported recessive inheritance. These variants were almost entirely absent from other breeds, and the allele frequency of the three candidate causal variants was less than 1% in the current Swiss Simmental population. This study identified three novel recessive alleles associated with syndromic forms of albinism or depigmentation, revealing unexpected heterogeneity. The investigation did not reveal any indications of possible dominant de novo mutations impacting protein coding genes including known candidate genes for depigmentation phenotypes. These findings possibly expand the list of pigmentation related genes in mammals, but further investigation is needed. We also highlight the biomedical relevance of investigating rare congenital disorders in livestock.
本研究旨在调查三头具有非典型白色被毛颜色的西门塔尔无关犊牛，采用基于三联体的全基因组测序方法确定潜在的遗传原因，并评估所鉴定变异在该品种中的流行情况。在源自瑞士的西门塔尔牛中，已经描述了几种影响被毛颜色的遗传等位基因，从浅黄色到红斑和白头。然而，在该品种中，尚未有遗传变异与几乎完全白色的被毛相关联。临床检查发现，所有三例西门塔尔牛的白色被毛颜色均存在不同的综合征性疾病，系谱记录表明为隐性遗传。对罕见的蛋白质改变变异进行筛选后，发现了一个独立的纯合变异，可能是每例的病因：病例1中TYR（NP_851344.1:p.Pro428Leu）的一个可能致病的错义变异，伴有1型眼皮肤白化病；病例2中GRID1（XP_024842694.1:p.Pro489His）的一个可能致病的错义变异，伴有身材矮小-听觉色素脱失综合征；病例3中RAD54B（NP_001179884.1:p.Ala722_Gly724delinsAsnLeuIlePheCys*）的一个意义不确定的移码变异，伴有多系统色素脱失综合征。通过桑格测序进行验证，证实了变异基因型，并且亲本杂合性支持隐性遗传。这些变异在其他品种中几乎完全不存在，在当前瑞士西门塔尔牛群体中，这三个候选致病变异的等位基因频率均小于1%。本研究确定了三个与白化病或色素脱失综合征形式相关的新的隐性等位基因，揭示了意想不到的异质性。该调查未发现任何可能影响蛋白质编码基因（包括已知的色素脱失表型候选基因）的显性新发突变的迹象。这些发现可能会扩大哺乳动物中与色素沉着相关基因的列表，但仍需进一步研究。我们还强调了研究家畜罕见先天性疾病的生物医学相关性。
