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

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.

Associated gene: