Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle.

Renae L Sieck,Stacy K Sanders,Patrick S Bedwell,Sichong Peng,Jack A Ward,Shi-Hua Xiang,David J Steffen,Anna M Fuller,Jessica L Petersen

doi:10.3390/genes11111246

Renae L Sieck, Stacy K Sanders + Show 7 more

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https://doi.org/10.3390/genes11111246

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Abstract

In spring 2020, six Hereford calves presented with congenital facial deformities attributed to a condition we termed mandibulofacial dysostosis (MD). Affected calves shared hallmark features of a variably shortened and/or asymmetric lower mandible and bilateral skin tags present 2–10 cm caudal to the commissure of the lips. Pedigree analysis revealed a single common ancestor shared by the sire and dam of each affected calf. Whole-genome sequencing (WGS) of 20 animals led to the discovery of a variant (Chr26 g. 14404993T>C) in Exon 3 of CYP26C1 associated with MD. This missense mutation (p.L188P), is located in an α helix of the protein, which the identified amino acid substitution is predicted to break. The implication of this mutation was further validated through genotyping 2 additional affected calves, 760 other Herefords, and by evaluation of available WGS data from over 2500 other individuals. Only the affected individuals were homozygous for the variant and all heterozygotes had at least one pedigree tie to the suspect founder. CYP26C1 plays a vital role in tissue-specific regulation of retinoic acid (RA) during embryonic development. Dysregulation of RA can result in teratogenesis by altering the endothelin-1 signaling pathway affecting the expression of Dlx genes, critical to mandibulofacial development. We postulate that this recessive missense mutation in CYP26C1 impacts the catalytic activity of the encoded enzyme, leading to excess RA resulting in the observed MD phenotype.

Highlights

Over 250 Mendelian traits in cattle are reported in the Online Mendelian Inheritance in Animals database
The tags were 0.5–2.0 cm long with a central dermal core that attached through a short, 1 cm dermal band to cartilage (Figure 1C). This cartilage extended to its origin at the zygomatic process of the temporal bone (Figure 1D)
When the bone was fractured during autopsy, a perfectly round 0.35 mm diameter tube of cartilage freely separated from the center of the bone (Figure 1E)

Summary

Introduction

Over 250 Mendelian traits in cattle are reported in the Online Mendelian Inheritance in Animals database (https://omia.org/home). Often deleterious syndromes in cattle are attributed to variants inherited in an autosomal recessive manner [1]. Due to this inheritance pattern, clinical signs of disease may not appear for many generations after the causal mutation originates. Artificial selection in livestock and the commonplace use of artificial insemination and embryo transfer can expedite widespread proliferation of a deleterious variant. Once a deleterious defect is identified, prompt identification of carrier animals is necessary to prevent economic loss. The significant impact of a single deleterious variant in livestock can be exemplified by a recessively inherited mutation in APAF1, Genes 2020, 11, 1246; doi:10.3390/genes11111246 www.mdpi.com/journal/genes

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