In other species: crab-eating macaque , Rhesus monkey , dog , rabbit , golden hamster

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 143890 (trait) , 606945 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: Hypercholesterolemia; see also OMIA:001160: Hyperlipidaemia

Species-specific name: familial hypercholesterolemia, recessive

Species-specific symbol: FH-r

Species-specific description: In addition to the occurrence of natural variants for this trait, variants have been created artificially: Genetically-modifed organism; GMO.

History: The paper by Hasler-Rapacz et al. (1998) was the first in any non-laboratory animal species to report the mapping of a disorder via a genome scan of microsatellites and the subsequent identification of a causal mutation via the positional comparative candidate gene strategy. This disorder was the first in non-laboratory animals to be investigated via the use of Transcription Activator-Like Effector Nucleases (TALENs) (Carlson et al., 2012) to create knockouts of the key gene (in this case, LDLR) (Carlson et al., 2012).

Mapping: A genome scan with microsatellites evenly spaced throughout the genome at around 20cM, conducted by Hasler-Rapacz et al. (1998) on 65 backcross pigs segregating for this disorder, showed that the gene for this disorder in pigs maps near to the centromere of chromosome 2, which is homologous to the region of human chromosome 19 containing the gene for low-density lipoprotein receptor (LDLR), a strong candidate for involvement in this disorder.

Molecular basis: Sequence analysis of the positional candidate LDLR gene by Hasler-Rapacz et al. (1998) in homozygous normal and affected pigs showed that the disorder is due to a single missense mutation (resulting in the amino-acid substitution Arg84Cys). The causal mutation was thus identified via the comparative positional candidate gene approach. Grunwald et al. (1999) confirmed the above likely causal variant. In a proof-of-principle study, Carlson et al. (2012) used Transcription Activator-Like Effector Nucleases (TALENs) to create cloned pigs with a range of mutations in the porcine LDLR gene, namely 289_290ins34, 285_287delATG, 211_292del128, 289_290del10 and 289_290insA. The phenotypes of these mutant pigs were not reported in this paper. Using homologous recombination to insert a premature stop codon and a neomycin-resistance casette into exon 4 of the LDLR gene in Yucatan miniature pigs, followed by somatic cell nuclear transfer and the mating of heterozygotes, Davis et al. (2014) created Yucatan miniature pigs completely lacking any functional LDLR. The authors report that this "new model of cardiovascular disease could be an important resource for developing and testing novel detection and treatment strategies for coronary and aortic atherosclerosis and its complications."

Genetic engineering: Yes - in addition to the occurrence of natural variants, variants have been created artificially, e.g. by genetic engineering or gene editing
Have human generated variants been created, e.g. through genetic engineering and gene editing

Associated gene: