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A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle

BACKGROUND: Bovine hereditary zinc deficiency (BHZD) is an autosomal recessive disorder of cattle, first described in Holstein-Friesian animals. Affected calves suffer from severe skin lesions and show a poor general health status. Recently, eight calves with the phenotypic appearance of BHZD have b...

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Autores principales: Jung, Simone, Pausch, Hubert, Langenmayer, Martin C, Schwarzenbacher, Hermann, Majzoub-Altweck, Monir, Gollnick, Nicole S, Fries, Ruedi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117962/
https://www.ncbi.nlm.nih.gov/pubmed/25052073
http://dx.doi.org/10.1186/1471-2164-15-623
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author Jung, Simone
Pausch, Hubert
Langenmayer, Martin C
Schwarzenbacher, Hermann
Majzoub-Altweck, Monir
Gollnick, Nicole S
Fries, Ruedi
author_facet Jung, Simone
Pausch, Hubert
Langenmayer, Martin C
Schwarzenbacher, Hermann
Majzoub-Altweck, Monir
Gollnick, Nicole S
Fries, Ruedi
author_sort Jung, Simone
collection PubMed
description BACKGROUND: Bovine hereditary zinc deficiency (BHZD) is an autosomal recessive disorder of cattle, first described in Holstein-Friesian animals. Affected calves suffer from severe skin lesions and show a poor general health status. Recently, eight calves with the phenotypic appearance of BHZD have been reported in the Fleckvieh cattle population. RESULTS: In spite of the similar disease phenotypes, SLC39A4, the gene responsible for BHZD in Holstein-Friesian was excluded as underlying gene for the disorder in the affected Fleckvieh calves. In order to identify the disease-associated region, genotypes of eight affected calves obtained with the Illumina BovineHD BeadChip comprising 777,962 SNPs were contrasted with the genotypes of 1,339 unaffected animals. A strong association signal was observed on chromosome 21 (P = 5.87 × 10(-89)). Autozygosity mapping in the eight affected animals revealed a common segment of extended homozygosity encompassing 1,023 kb (BTA 21: 70,550,045 - 71,573,501). This region contains 17 genes/transcripts, among them two genes encoding gastro-intestinal zinc transporters (CRIP1, CRIP2). However, no mutation that was compatible with recessive inheritance could be detected in these candidate genes. One of the affected calves was re-sequenced together with 42 unaffected Fleckvieh animals. Analysis of the sequencing data revealed a nonsense mutation (p.W215X) in a phospholipase encoding gene (PLD4) as candidate causal polymorphism. To confirm the causality, genotypes of the p.W215X-mutation were obtained from 3,650 animals representing three different breeds. None of the unaffected animals was homozygous for the defect allele, while all eight affected calves were homozygous. The deleterious effect of the mutation is manifested in a significantly lower survival rate of descendants from risk matings when compared with the survival rate of descendants from non-risk matings. The deleterious allele has an estimated frequency of 1.1% in the Fleckvieh population. CONCLUSION: Our results provide strong evidence that a newly identified recessive disorder in the Fleckvieh population is caused by a nonsense mutation in PLD4, most likely resulting in an impaired function of the encoded protein. Although the phenotype of affected calves strongly resembles BHZD, a zinc deficiency resulting from malabsorption is unlikely to be responsible for the diseased Fleckvieh calves. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-623) contains supplementary material, which is available to authorized users.
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spelling pubmed-41179622014-08-05 A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle Jung, Simone Pausch, Hubert Langenmayer, Martin C Schwarzenbacher, Hermann Majzoub-Altweck, Monir Gollnick, Nicole S Fries, Ruedi BMC Genomics Research Article BACKGROUND: Bovine hereditary zinc deficiency (BHZD) is an autosomal recessive disorder of cattle, first described in Holstein-Friesian animals. Affected calves suffer from severe skin lesions and show a poor general health status. Recently, eight calves with the phenotypic appearance of BHZD have been reported in the Fleckvieh cattle population. RESULTS: In spite of the similar disease phenotypes, SLC39A4, the gene responsible for BHZD in Holstein-Friesian was excluded as underlying gene for the disorder in the affected Fleckvieh calves. In order to identify the disease-associated region, genotypes of eight affected calves obtained with the Illumina BovineHD BeadChip comprising 777,962 SNPs were contrasted with the genotypes of 1,339 unaffected animals. A strong association signal was observed on chromosome 21 (P = 5.87 × 10(-89)). Autozygosity mapping in the eight affected animals revealed a common segment of extended homozygosity encompassing 1,023 kb (BTA 21: 70,550,045 - 71,573,501). This region contains 17 genes/transcripts, among them two genes encoding gastro-intestinal zinc transporters (CRIP1, CRIP2). However, no mutation that was compatible with recessive inheritance could be detected in these candidate genes. One of the affected calves was re-sequenced together with 42 unaffected Fleckvieh animals. Analysis of the sequencing data revealed a nonsense mutation (p.W215X) in a phospholipase encoding gene (PLD4) as candidate causal polymorphism. To confirm the causality, genotypes of the p.W215X-mutation were obtained from 3,650 animals representing three different breeds. None of the unaffected animals was homozygous for the defect allele, while all eight affected calves were homozygous. The deleterious effect of the mutation is manifested in a significantly lower survival rate of descendants from risk matings when compared with the survival rate of descendants from non-risk matings. The deleterious allele has an estimated frequency of 1.1% in the Fleckvieh population. CONCLUSION: Our results provide strong evidence that a newly identified recessive disorder in the Fleckvieh population is caused by a nonsense mutation in PLD4, most likely resulting in an impaired function of the encoded protein. Although the phenotype of affected calves strongly resembles BHZD, a zinc deficiency resulting from malabsorption is unlikely to be responsible for the diseased Fleckvieh calves. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-623) contains supplementary material, which is available to authorized users. BioMed Central 2014-07-22 /pmc/articles/PMC4117962/ /pubmed/25052073 http://dx.doi.org/10.1186/1471-2164-15-623 Text en © Jung et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Jung, Simone
Pausch, Hubert
Langenmayer, Martin C
Schwarzenbacher, Hermann
Majzoub-Altweck, Monir
Gollnick, Nicole S
Fries, Ruedi
A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle
title A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle
title_full A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle
title_fullStr A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle
title_full_unstemmed A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle
title_short A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle
title_sort nonsense mutation in pld4 is associated with a zinc deficiency-like syndrome in fleckvieh cattle
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117962/
https://www.ncbi.nlm.nih.gov/pubmed/25052073
http://dx.doi.org/10.1186/1471-2164-15-623
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