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

Abstract

BackgroundBovine 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.ResultsIn 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.ConclusionOur 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 materialThe online version of this article (doi:10.1186/1471-2164-15-623) contains supplementary material, which is available to authorized users.

A missense mutation inTUBD1is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle

“…The joint analysis of homozygosity depletion and insemination and rearing data revealed a 1.14 Mb haplotype located between 10,694,269 bp and 11,833,182 bp on BTA19 as the most likely interval harboring the causal mutation, which agrees with previous findings [17,19]. [10,18,26,30].…”

The phospholipase D superfamily as therapeutic targets

“…Interest has become increasingly focused on PLD1 and PLD2 in the context of cancer, cardiovascular, neurodegenerative, and infectious disease, while loss of function of PLD3 has been linked to Alzheimer’s disease [7], loss of PLD4 function to autoimmune disease [4, 8, 9], and PLD6 has been found to be required for spermatogenesis [10]. Mice lacking PLD5 have been generated by the International Knockout Mouse Consortium program and subjected to a standardized phenotypic screen involving 25 tests, but no significant abnormalities were observed [11].…”

Microglial phospholipase D4 deficiency influences myelination during brain development

“…Recently, it was reported that the PLD4 gene is an indicator of susceptibility to certain autoimmune diseases in a Japanese population, 4) and a nonsense mutation in PLD4 gene was shown to cause a zinc deficiency-like syndrome in cattle. 5) However, the roles of PLD4 in these disorders as well as in normal brain development are still unknown.…”