Abstract
BackgroundThe long bone abnormality (lbab) mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488.ResultsA genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents.ConclusionA single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.
Highlights
The long bone abnormality mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones
[3] To explore causative genetic factor(s) for the development of achondroplasia in animal models, we focused on a novel spontaneous model of long bone abnormality called lbab mouse, which was originally found in the PL/J strain at The Jackson Laboratory
Target region of the mutation in lbab locus Previous genetic analysis showed that the lbab mutation is located on mouse chromosome 1 (Chr 1) and is flanked by molecular markers D1Mit9 and D1Mit488 [4]
Summary
The long bone abnormality (lbab) mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Achondroplasia (short-limbed dwarfism) is the most common cause of human dwarfism [2], and it accounts for 70% of dwarfism cases [3] To explore causative genetic factor(s) for the development of achondroplasia in animal models, we focused on a novel spontaneous model of long bone abnormality called lbab mouse, which was originally found in the PL/J strain at The Jackson Laboratory (page number not for citation purposes). The genetic locus responsible for the phenotype has previously been mapped to chromosome 1 (Chr 1) between markers D1Mit and D1Mit488 (53.5 cM) at TJL [4], but the responsible gene and the nature of mutation remained unclear. We developed an alternative, sequence-based, positional candidate cloning approach to bypass this bottleneck of cloning, and we have successfully identified several mutated genes in different mouse spontaneous mutants by applying this strategy [6,7]. We describe the detailed process of our cloning and validation
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