Abstract
Inherited rickets of Corriedale sheep is characterized by decreased growth rate, thoracic lordosis and angular limb deformities. Previous outcross and backcross studies implicate inheritance as a simple autosomal recessive disorder. A genome wide association study was conducted using the Illumina OvineSNP50 BeadChip on 20 related sheep comprising 17 affected and 3 carriers. A homozygous region of 125 consecutive single-nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 6 Mb on ovine chromosome 6. Among 35 candidate genes in this region, the dentin matrix protein 1 gene (DMP1) was sequenced to reveal a nonsense mutation 250C/T on exon 6. This mutation introduced a stop codon (R145X) and could truncate C-terminal amino acids. Genotyping by PCR-RFLP for this mutation showed all 17 affected sheep were “T T” genotypes; the 3 carriers were “C T”; 24 phenotypically normal related sheep were either “C T” or “C C”; and 46 unrelated normal control sheep from other breeds were all “C C”. The other SNPs in DMP1 were not concordant with the disease and can all be ruled out as candidates. Previous research has shown that mutations in the DMP1 gene are responsible for autosomal recessive hypophosphatemic rickets in humans. Dmp1_knockout mice exhibit rickets phenotypes. We believe the R145X mutation to be responsible for the inherited rickets found in Corriedale sheep. A simple diagnostic test can be designed to identify carriers with the defective “T” allele. Affected sheep could be used as animal models for this form of human rickets, and for further investigation of the role of DMP1 in phosphate homeostasis.
Highlights
Rickets is a metabolic bone disease in humans and animals with most cases caused by a nutritional deficiency of either vitamin D or phosphorus
A homozygous region of 125 consecutive single-nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 6 Mb on ovine chromosome 6
autosomal dominant hypophosphatemic rickets (ADHR) is caused by gain of function mutation leading to increased activity of fibroblast growth factor 23 encoded by gene FGF23 [7], and mutations in the dentin matrix protein 1 gene (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) have been identified in autosomal recessive hypophosphataemic rickets type 1 and 2, respectively [8], [9], [10]
Summary
Rickets is a metabolic bone disease in humans and animals with most cases caused by a nutritional deficiency of either vitamin D or phosphorus. This disease leads to softening and weakening of bone caused by defective mineralization of cartilage at sites of endochondral ossification and potentially causes fractures and limb deformities [1], [2], [3]. ADHR is caused by gain of function mutation leading to increased activity of fibroblast growth factor 23 encoded by gene FGF23 [7], and mutations in the dentin matrix protein 1 gene (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) have been identified in autosomal recessive hypophosphataemic rickets type 1 and 2, respectively [8], [9], [10]. Loss of function mutations in the vitamin D receptor gene (VDR) are the genetic basis for vitamin D-dependent rickets type II (VDDR-II), which is called hereditary vitamin D - resistant rickets (HVDRR) [13], [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
