Cholesterol deficiency, APOB-related

Phene ID

3780

Name

Cholesterol deficiency, APOB-related

Phene Name

Holstein cholesterol deficiency

OMIA ID

1965

Species ID

9913

Characterised

Yes

Characterised Year

2016

[FN thanks Ekkehard Schütz for feedback on an earlier version of the text on this page]

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."

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."