OMIA:001965-9913 : Cholesterol deficiency, APOB-related in Bos taurus
Categories: Digestive / alimentary phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive lethal
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2016
Cross-species summary: HYPOBETALIPOPROTEINEMIA, FAMILIAL
Species-specific name: Holstein cholesterol deficiency
Species-specific symbol: HCD; CDH
Species-specific description: [FN thanks Ekkehard Schütz for feedback on an earlier version of the text on this page]
History: Kipp et al. (2015) reported a ~2.7Mb haplotype on chromosome BTA11 that is strongly associated with chronic diarrhea in calves, leading to death; and with hypocholesterolaemia.
Inheritance: Häfliger et al. (2019): "As only some APOB heterozygotes show the clinical CD phenotype, we assume that the penetrance is reduced in heterozygotes compared to the fully penetrant effect observed in homozygotes. We conclude that APOB-associated CD represents most likely an incomplete dominant inherited metabolic disease with incomplete penetrance in heterozygotes."
Mapping: By conducting a GWAS on 23 affected and 11,177 normal German Holstein calves, each genotyped with the Illumina 54k SNP chip, Kipp et al. (2015) mapped this disorder to chromosome BTA11. Subsequent homozygosity mapping of this chromosome narrowed the candidate region down to a haplotype in the region of approximately 74.4 - 77.1 Mb. Interestingly, one of the human causal genes (APOB, for hypobetalipoproteinemia, familial, 1; OMIM 615558) maps very near to the causal cattle haplotype.
Molecular basis: Menzi et al. (2016) "resequenced the entire genomes of an affected calf and a healthy partially inbred male carrying one copy of the critical 2.24-Mb chromosome 11 segment [identified by Kipp et al., 2015] in its ancestral state and one copy of the same segment with the cholesterol deficiency mutation. [They] detected a single structural variant, homozygous in the affected case and heterozygous in the non-affected carrier male. The genetic makeup of this key animal provides extremely strong support for the causality of this mutation. The mutation represents a 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)]. This finding was further supported by RNA sequencing of the liver transcriptome of an affected calf. "
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 (black and white) (Cattle) (VBO_0000237).
|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.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|731||Holstein (black and white) (Cattle)||Holstein cholesterol deficiency||APOB||insertion, gross (>20)||Naturally occurring variant||11||"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|
Cite this entry
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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