OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia

J Genet Genomics. 2019 Aug 20;46(8):379-387. doi: 10.1016/j.jgg.2019.06.006. Epub 2019 Aug 13.

Abstract

Oxysterol binding protein like 2 (OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotype-phenotype associations, the OSBPL2-disrupted Bama miniature (BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer (SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss (HL) with degeneration/apoptosis of cochlea hair cells (HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet (HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss (NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.

Keywords: Bama miniature pig; Hearing loss; Hypercholesterolaemia; OSBPL2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • CRISPR-Cas Systems
  • Disease Models, Animal
  • Embryo Transfer
  • Genetic Association Studies
  • Genetic Linkage
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genotype
  • Hearing Loss / diagnosis
  • Hearing Loss / genetics*
  • Humans
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / genetics*
  • Mutation*
  • Phenotype
  • Receptors, Steroid / genetics*
  • Swine
  • Swine, Miniature

Substances

  • OSBPL2 protein, human
  • Receptors, Steroid