A novel nonsense mutation in DMP1 gene identified by a genome-wide association study is responsible for inherited rickets in Corriedale sheep

ABSTRACT: Inherited rickets of Corriedale sheep is characterized by decreased growth rate, thoracic lordosis and angular limb deformities. Previous outcross and backcross studies suggest it is a simple autosomal recessive disorder. A genome wide association study was conducted using the Illumina OvineSNP50 BeadChip on 20 related sheep including 17 affected and 3 carriers. A homozygous region of 199 consecutive single-nucleotide polymorphism (SNP) loci was identified in all the affected sheep, covering a region of 10Mbp on ovine chromosome 6. Among 91 candidate genes in this region, exon 6 of the dentin matrix protein 1 gene (DMP1) was sequenced to reveal 9 SNPs including a nonsense mutation 253T/C which introduced a stop codon (R145X) and could truncate C-terminal amino acids. Genotyping by PCR-RFLP for this mutation showed that, all 17 affected sheep were “T T” genotypes and the 27 phenotypically normal sheep were either “C T” or “C C”. This locus is not in complete linkage disequilibrium with the other 8 SNPs that can all be ruled out as candidates. Previous research has shown that mutations in DMP1 gene are responsible for autosomal recessive hypophosphatemic rickets in humans. Dmp1_knockout mice also 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” alleles. 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

ORGANISM(S): Ovis aries

PROVIDER: GSE26310 | GEO | 2012/01/01

SECONDARY ACCESSION(S): PRJNA136753

REPOSITORIES: GEO