OMIA 001965-9913 : Holstein cholesterol deficiency in Bos taurus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 615558

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive Lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

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.

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".

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

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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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

References


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.
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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  • Created by Frank Nicholas on 06 Aug 2015
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