Carpinelli Marina R, Wicks Ian P, Sims Natalie A, O'Donnell Kristy, Hanzinikolas Katherine, Burt Rachel, Foote Simon J, Bahlo Melanie, Alexander Warren S, Hilton Douglas J
Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria, Australia.
Am J Pathol. 2002 Nov;161(5):1925-33. doi: 10.1016/S0002-9440(10)64468-9.
We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.
我们描述了一只小鼠的临床、遗传、生化和分子特征，该小鼠出现在用化学诱变剂乙基硝基脲进行的随机诱变筛选的第一代（G(1)）中。观察到该小鼠具有以X连锁显性遗传模式遗传的骨骼异常。致病突变被命名为骨骼异常1（Ska1），它被证明是位于X染色体上的与内肽酶具有同源性的磷酸盐调节基因（Phex）第8外显子之后的剪接供体位点的单碱基对突变。这个点突变导致Phex mRNA跳过第8外显子，引起低磷血症和佝偻病特征。这种实验诱导的表型反映了人类的X连锁低磷血症；直接证实了Phex在磷酸盐稳态、正常骨骼发育和佝偻病中的作用；并说明了诱变在探索人类疾病动物模型方面的作用。
