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

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 th...

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Autores principales: Sieck, Renae L., Fuller, Anna M., Bedwell, Patrick S., Ward, Jack A., Sanders, Stacy K., Xiang, Shi-Hua, Peng, Sichong, Petersen, Jessica L., Steffen, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690606/
https://www.ncbi.nlm.nih.gov/pubmed/33105751
http://dx.doi.org/10.3390/genes11111246
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author Sieck, Renae L.
Fuller, Anna M.
Bedwell, Patrick S.
Ward, Jack A.
Sanders, Stacy K.
Xiang, Shi-Hua
Peng, Sichong
Petersen, Jessica L.
Steffen, David J.
author_facet Sieck, Renae L.
Fuller, Anna M.
Bedwell, Patrick S.
Ward, Jack A.
Sanders, Stacy K.
Xiang, Shi-Hua
Peng, Sichong
Petersen, Jessica L.
Steffen, David J.
author_sort Sieck, Renae L.
collection PubMed
description 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.
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spelling pubmed-76906062020-11-27 Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle Sieck, Renae L. Fuller, Anna M. Bedwell, Patrick S. Ward, Jack A. Sanders, Stacy K. Xiang, Shi-Hua Peng, Sichong Petersen, Jessica L. Steffen, David J. Genes (Basel) Article 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. MDPI 2020-10-22 /pmc/articles/PMC7690606/ /pubmed/33105751 http://dx.doi.org/10.3390/genes11111246 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sieck, Renae L.
Fuller, Anna M.
Bedwell, Patrick S.
Ward, Jack A.
Sanders, Stacy K.
Xiang, Shi-Hua
Peng, Sichong
Petersen, Jessica L.
Steffen, David J.
Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle
title Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle
title_full Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle
title_fullStr Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle
title_full_unstemmed Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle
title_short Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle
title_sort mandibulofacial dysostosis attributed to a recessive mutation of cyp26c1 in hereford cattle
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690606/
https://www.ncbi.nlm.nih.gov/pubmed/33105751
http://dx.doi.org/10.3390/genes11111246
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