OMIA 000499-9823 : Hypercholesterolaemia in Sus scrofa

In other species: dog , rabbit

Possibly relevant human trait(s) and/or gene(s) (MIM number): 143890

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1998

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 Haslerrapacz 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."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
LDLR low density lipoprotein receptor Sus scrofa 2 NC_010444.4 (69828348..69864823) LDLR 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
FH-r strain Hypercholesterolaemia LDLR missense 2 c.250C>T p. Arg84Cys 1998 9556295

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 Leroy, G., Besbes, B., Boettcher, P., Hoffmann, I., Capitan, A., Baumung, R. :
Rare phenotypes in domestic animals: unique resources for multiple applications. Anim Genet 47:141-53, 2016. Pubmed reference: 26662214. DOI: 10.1111/age.12393.
2014 Davis, B.T., Wang, X.J., Rohret, J.A., Struzynski, J.T., Merricks, E.P., Bellinger, D.A., Rohret, F.A., Nichols, T.C., Rogers, C.S. :
Targeted Disruption of LDLR Causes Hypercholesterolemia and Atherosclerosis in Yucatan Miniature Pigs. PLoS One 9:e93457, 2014. Pubmed reference: 24691380. DOI: 10.1371/journal.pone.0093457.
2013 Bahls, M., Bidwell, C.A., Hu, J., Tellez, A., Kaluza, G.L., Granada, J.F., Krueger, C.G., Reed, J.D., Laughlin, M.H., Van Alstine, W.G., Newcomer, S.C. :
Gene expression differences during the heterogeneous progression of peripheral atherosclerosis in familial hypercholesterolemic swine. BMC Genomics 14:443, 2013. Pubmed reference: 23822099. DOI: 10.1186/1471-2164-14-443.
Hamamdzic, D., Wilensky, R.L. :
Porcine models of accelerated coronary atherosclerosis: role of diabetes mellitus and hypercholesterolemia. J Diabetes Res 2013:761415, 2013. Pubmed reference: 23844374. DOI: 10.1155/2013/761415.
2012 Carlson, D.F., Tan, W., Lillico, S.G., Stverakova, D., Proudfoot, C., Christian, M., Voytas, D.F., Long, C.R., Whitelaw, C.B., Fahrenkrug, S.C. :
Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci U S A 109:17382-7, 2012. Pubmed reference: 23027955. DOI: 10.1073/pnas.1211446109.
2009 Pena, R.N., Cánovas, A., Varona, L., Díaz, I., Gallardo, D., Ramírez, O., Noguera, J.L., Quintanilla, R. :
Nucleotide sequence and association analysis of pig apolipoprotein-B and LDL-receptor genes. Anim Biotechnol 20:110-23, 2009. Pubmed reference: 19544207. DOI: 10.1080/10495390902892518.
2002 Krier, J.D., Rodriguez-Porcel, M., Best, P.J.M., Romero, J.C., Lerman, A., Lerman, L.O. :
Vascular responses in vivo to 8-epi PGF(2 alpha) in normal and hypercholesterolemic pigs American Journal of Physiology - Regulatory Integrative & Comparative Physiology 283:R303-R308, 2002.
2001 Martinez-Gonzalez, J., Alfon, J., Berrozpe, M., Badimon, L. :
HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels Atherosclerosis 159:27-33, 2001. Pubmed reference: 11689203.
1999 Grunwald, K.A.A., Schueler, K., Uelmen, P.J., Lipton, B.A., Kaiser, M., Buhman, K., Attie, A.D. :
Identification of a novel Arg -> Cys mutation in the LDL receptor that contributes to spontaneous hypercholesterolemia in pigs Journal of Lipid Research 40:475-485, 1999. Pubmed reference: 10064736.
1998 Hasler-Rapacz, J., Ellegren, H., Fridolfsson, A.K., Kirkpatrick, B., Kirk, S., Andersson, L., Rapacz, J. :
Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolaemia in swine American Journal of Medical Genetics 76:379-386, 1998. Pubmed reference: 9556295.
1995 Hasler-Rapacz, J., Prescott, M.F., Vonlindenreed, J., Rapacz, J.M., Hu, Z.L., Rapacz, J. :
Elevated concentrations of plasma lipids and apolipoproteins B, C-III, and E are associated with the progression of coronary artery disease in familial hypercholesterolemic swine Arteriosclerosis Thrombosis and Vascular Biology 15:583-592, 1995.
Smith, M.J., Allen, K.G.D., Norman, J.F., Harris, M.A., Miller, C.W. :
Low-dose aspirin does not attenuate platelet aggregation or atherosclerosis in miniature swine but decreases production of aortic wall prostacyclin Prostaglandins Leukotrienes & Essential Fatty Acids 53:331-340, 1995.
1994 Aiello, R.J., Nevin, D.N., Ebert, D.L., Uelmen, P.J., Kaiser, M.E., Maccluer, J.W., Blangero, J., Dyer, T.D., Attie, A.D. :
Apolipoprotein B and a Second Major Gene Locus Contribute to Phenotypic Variation of Spontaneous Hypercholesterolemia in Pigs Arteriosclerosis and Thrombosis 14:409-419, 1994. Pubmed reference: 8123646.
Hasler-Rapacz, J.O., Nichols, T.C., Griggs, T.R., Bellinger, D.A., Rapacz, J. :
Familial and diet-induced hypercholesterolemia in swine - Lipid, ApoB, and ApoA-I concentrations and distributions in plasma and lipoprotein subfractions Arteriosclerosis and Thrombosis 14:923-930, 1994. Pubmed reference: 8199183.
1993 Davis, AM., White, BA., Wheeler, MB. :
A TaqI RFLP at the porcine low density lipoprotein receptor (LDLR) locus. Anim Genet 24:330, 1993. Pubmed reference: 7902045.
Purtell, C., Maeda, N., Ebert, D.L., Kaiser, M., Lundkatz, S., Sturley, S.L., Kodoyianni, V., Grundwald, K., Nevin, D.N., Aiello, R.J., Attie, A.D. :
Nucleotide Sequence Encoding the Carboxyl-Terminal Half of Apolipoprotein-B from Spontaneously Hypercholesterolemic Pigs (Vol 34, Pg 1323, 1993) Journal of Lipid Research 34:1832, 1993.
Purtell, C., Maeda, N., Ebert, D.L., Kaiser, M., Lundkatz, S., Sturley, S.L., Kodoyianni, V., Grunwald, K., Nevin, D.N., Aiello, R.J., Attie, A.D. :
Nucleotide Sequence Encoding the Carboxyl-Terminal Half of Apolipoprotein-B from Spontaneously Hypercholesterolemic Pigs Journal of Lipid Research 34:1323-1335, 1993. Pubmed reference: 8409766.
1992 Cooper, S.T., Aiello, R.J., Checovich, W.J., Attie, A.D. :
Low Density Lipoprotein Heterogeneity in Spontaneously Hypercholesterolemic Pigs Molecular and Cellular Biochemistry 113:133-140, 1992. Pubmed reference: 1518504.
Lacko, A.G., Lee, S.M., Mirshahi, I., Hasler-Rapacz, J., Kudchodkar, B.J., Rapacz, J. :
Decreased Lecithin - Cholesterol Acyltransferase Activity in the Plasma of Hypercholesterolemic Pigs Lipids 27:266-269, 1992. Pubmed reference: 1518383.
1991 Checovich, W.J., Aiello, R.J., Attie, A.D. :
Overproduction of a Buoyant Low Density Lipoprotein Subspecies in Spontaneously Hypercholesterolemic Mutant Pigs Arteriosclerosis and Thrombosis 11:351-361, 1991. Pubmed reference: 1998653.
Prescott, M.F., Mcbride, C.H., Hasler-Rapacz, J., Vonlinden, J., Rapacz, J. :
Development of Complex Atherosclerotic Lesions in Pigs with Inherited Hyper-LDL Cholesterolemia Bearing Mutant Alleles for Apolipoprotein-B American Journal of Pathology 139:139-147, 1991. Pubmed reference: 1853929.
1990 Lee, D.M., Mok, T., Hasler-Rapacz, J., Rapacz, J. :
Concentrations and Compositions of Plasma Lipoprotein Subfractions of Lpb5-Lpu1 Homozygous and Heterozygous Swine with Hypercholesterolemia Journal of Lipid Research 31:839-847, 1990. Pubmed reference: 2380632.

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