Department of Animal Science and Center for Integrated Animal Genomics, Iowa State University, Ames, Iowa, United States of America.
PLoS One. 2011;6(7):e21739. doi: 10.1371/journal.pone.0021739. Epub 2011 Jul 1.
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.
科里代尔羊遗传性佝偻病的特征是生长速度下降、胸腰椎前凸和肢角度畸形。先前的杂交和回交研究表明，这种遗传是一种简单的常染色体隐性疾病。我们使用 Illumina OvineSNP50 BeadChip 在 20 只相关绵羊中进行了全基因组关联研究，其中包括 17 只受影响的绵羊和 3 只携带者。在所有受影响的绵羊中都发现了一个 125 个连续单核苷酸多态性 (SNP) 位点的纯合区域，该区域覆盖了绵羊 6 号染色体上 6Mb 的区域。在这个区域的 35 个候选基因中，对牙本质基质蛋白 1 基因 (DMP1) 进行测序，结果显示在第 6 外显子上存在 250C/T 的无义突变。该突变引入了一个终止密码子 (R145X)，可能会截断 C 末端的氨基酸。对该突变进行的 PCR-RFLP 基因分型显示，所有 17 只受影响的绵羊均为“TT”基因型；3 只携带者为“CT”；24 只表型正常的相关绵羊为“CT”或“CC”；46 只来自其他品种的无关正常对照绵羊均为“CC”。DMP1 中的其他 SNP 与疾病不一致，可以全部排除作为候选基因。先前的研究表明，DMP1 基因突变是导致人类常染色体隐性低磷佝偻病的原因。Dmp1_knockout 小鼠表现出佝偻病表型。我们认为 R145X 突变是导致科里代尔羊遗传性佝偻病的原因。可以设计一种简单的诊断测试来识别携带缺陷“T”等位基因的携带者。受影响的绵羊可以作为这种人类佝偻病的动物模型，并进一步研究 DMP1 在磷酸盐稳态中的作用。
