OMIA 001965-9913 : Holstein cholesterol deficiency in Bos taurus
Charlier (2016) confirmed this result, but with a different estimate of the size of the insertion: "the causative mutation corresponds to the sense insertion of a ~7kb full-length bos Taurus endogenous retroviral element (BoERV) in exon 5 of the Apolipoprotein B gene (APOB), resulting in complete transcriptional termination downstream to the insertion point."
The 1.3kb insertion result was confirmed by Schütz et al. (2016), who reported that the causal mutation is "a 1.3kbp insertion of an endogenous retrovirus (ERV2-1-LTR_BT) into exon 5 of the APOB gene at BTA11:77,959kb. The insertion is flanked by 6bp target site duplications as described for insertions mediated by retroviral integrases. A premature stop codon in the open reading frame of APOB is generated, resulting in a truncation of the protein to a length of only <140 amino acids".
Gross et al. (2016) reported that the causal mutation affects "lipid metabolism in affected [homozygous] Holstein calves and adult [heterozygous] breeding bulls. Besides cholesterol, the concentrations of PL, TAG, and lipoproteins also were distinctly reduced in homozygous and heterozygous carriers of the mutation. Beyond malabsorption of dietary lipids, deleterious effects of apolipoprotein B deficiency on hepatic lipid metabolism, steroid biosynthesis, and cell membrane function can be expected, which may result in unspecific symptoms of reduced fertility, growth, and health".
Gross et al. (2019) reported that "The low cholesterol concentrations associated with the APOB mutation in heterozygous carriers are not because of a primary deficiency of cholesterol at a cellular level, as the term "cholesterol deficiency" suggests, but rather a consequence of reduced capacity for its transport in circulation. Overall, the data of the present study suggest that, despite the presence of the APOB mutation, cholesterol is not limiting for animals' metabolic adaptation and performance in heterozygous Holstein cows."Prevalence: Kipp et al. (2015) estimated that around 3,400 Holstein calves homozygous for this haplotype are born each year in Germany, giving a carrier frequency of around 8.7%.
Using direct PCR analyses Schütz et al. (2016) estimated the carrier frequency in cattle born between 2012 and 2015 in Germany to be approximately 12.5%.Breed: Holstein. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|APOB||apolipoprotein B||Bos taurus||11||NC_037338.1 (77885988..77927967)||APOB||Homologene, Ensembl, NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Holstein||Holstein cholesterol deficiency||APOB||insertion, gross (>20)||"1.3kb insertion of a transposable LTR element (ERV2-1) in the coding sequence of the APOB gene, which leads to truncated transcripts and aberrant splicing [p.Gly135ValfsX10)]"||2016||26763170|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2019||Gross, J.J., Schwinn, A.C., Schmitz-Hsu, F., Barenco, A., Neuenschwander, T.F., Drögemüller, C., Bruckmaier, R.M., Gross, J.J., Schwinn, A.C., Schmitz-Hsu, F., Barenco, A., Neuenschwander, T.F., Drögemüller, C., Bruckmaier, R.M. :|
|The APOB loss-of-function mutation of Holstein dairy cattle does not cause a deficiency of cholesterol but decreases the capacity for cholesterol transport in circulation. J Dairy Sci 102:10564-10572, 2019. Pubmed reference: 31477289. DOI: 10.3168/jds.2019-16852.|
|Häfliger, I.M., Hofstetter, S., Mock, T., Stettler, M.H., Meylan, M., Mehinagic, K., Stokar-Regenscheit, N., Drögemüller, C. :|
|APOB-associated cholesterol deficiency in Holstein cattle is not a simple recessive disease. Anim Genet 50:372-375, 2019. Pubmed reference: 31215050. DOI: 10.1111/age.12801.|
|2016||Charlier, C. :|
|The Role of Mobile Genetic Elements in the Bovine Genome. Plant and Animal Genome Conference XXIV, January 9-13, 2016 San Diego Abstract W636:, 2016.|
|Cole, J.B., Null, D.J., VanRaden, P.M. :|
|Phenotypic and genetic effects of recessive haplotypes on yield, longevity, and fertility. J Dairy Sci 99:7274-88, 2016. Pubmed reference: 27394947. DOI: 10.3168/jds.2015-10777.|
|Duff, J.P., Passant, S., Wessels, M., Charlier, C., Hateley, G., Irvine, R.M. :|
|Cholesterol deficiency causing calf illthrift and diarrhoea. Vet Rec 178:424-5, 2016. Pubmed reference: 27103694. DOI: 10.1136/vr.i2265.|
|Gross, J.J., Schwinn, A.C., Schmitz-Hsu, F., Menzi, F., Drögemüller, C., Albrecht, C., Bruckmaier, R.M. :|
|Rapid Communication: Cholesterol deficiency-associated APOB mutation impacts lipid metabolism in Holstein calves and breeding bulls. J Anim Sci 94:1761-1766, 2016. Pubmed reference: 27136033. DOI: 10.2527/jas.2016-0439.|
|Kipp, S., Segelke, D., Schierenbeck, S., Reinhardt, F., Reents, R., Wurmser, C., Pausch, H., Fries, R., Thaller, G., Tetens, J., Pott, J., Haas, D., Raddatz, B.B., Hewicker-Trautwein, M., Proios, I., Schmicke, M., Grünberg, W. :|
|Identification of a haplotype associated with cholesterol deficiency and increased juvenile mortality in Holstein cattle. J Dairy Sci 99:8915-8931, 2016. Pubmed reference: 27614835. DOI: 10.3168/jds.2016-11118.|
|Menzi, F., Besuchet-Schmutz, N., Fragnière, M., Hofstetter, S., Jagannathan, V., Mock, T., Raemy, A., Studer, E., Mehinagic, K., Regenscheit, N., Meylan, M., Schmitz-Hsu, F., Drögemüller, C. :|
|A transposable element insertion in APOB causes cholesterol deficiency in Holstein cattle. Anim Genet 47:253-7, 2016. Pubmed reference: 26763170. DOI: 10.1111/age.12410.|
|Mock, T., Mehinagic, K., Menzi, F., Studer, E., Oevermann, A., Stoffel, M.H., Drögemüller, C., Meylan, M., Regenscheit, N. :|
|Clinicopathological Phenotype of Autosomal Recessive Cholesterol Deficiency in Holstein Cattle. J Vet Intern Med 30:1369-75, 2016. Pubmed reference: 27279263. DOI: 10.1111/jvim.13976.|
|Saleem, S., Heuer, C., Sun, C., Kendall, D., Moreno, J., Vishwanath, R. :|
|Technical note: The role of circulating low-density lipoprotein levels as a phenotypic marker for Holstein cholesterol deficiency in dairy cattle. J Dairy Sci :, 2016. Pubmed reference: 27108167. DOI: 10.3168/jds.2015-10805.|
|Schütz, E., Wehrhahn, C., Wanjek, M., Bortfeld, R., Wemheuer, W.E., Beck, J., Brenig, B. :|
|The Holstein Friesian Lethal Haplotype 5 (HH5) Results from a Complete Deletion of TFB1M and Cholesterol Deficiency (CDH) from an ERV-(LTR) Insertion into the Coding Region of APOB. PLoS One 11:e0154602, 2016. Pubmed reference: 27128314. DOI: 10.1371/journal.pone.0154602.|
|2015||Kipp, S., Segelke, D., Schierenbeck, S., Reinhardt, F., Reents, R., Wurmser, C., Pausch, H., Fries, R., Thaller, G., Tetens, J., Pott, J., Piechotta, M., Grünberg, W. :|
|A new Holstein haplotype affecting calf survival. Interbull annual meeting, Orlando, FL, July 11, 2015; Interbull Bulletin No. 49 :49-53, 2015.|
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