Abstract
The transcription factor TBX3 plays critical roles in development and TBX3 mutations in humans cause Ulnar-mammary syndrome. Efforts to understand how altered TBX3 dosage and function disrupt the development of numerous structures have been hampered by embryonic lethality of mice bearing presumed null alleles. We generated a novel conditional null allele of Tbx3: after Cre-mediated recombination, no mRNA or protein is detectable. In contrast, a putative null allele in which exons 1-3 are deleted produces a truncated protein that is abnormally located in the cytoplasm. Heterozygotes and homozygotes for this allele have different phenotypes than their counterparts bearing a true null allele. Our observations with these alleles in mice, and the different types of TBX3 mutations observed in human ulnar-mammary syndrome, suggest that not all mutations observed in humans generate functionally null alleles. The possibility that mechanisms in addition to TBX3 haploinsufficiency may cause UMS or other malformations merits investigation in the human UMS population.
Highlights
The transcription factor TBX3 is critical for human development: heterozygotes bearing point, deletion and insertion mutations in TBX3 have ulnar-mammary syndrome (UMS) consisting of congenital limb defects, apocrine and mammary gland hypoplasia, and dental and genital abnormalities [1]
We show that deletion of the T-box encoding region does not inevitably generate a null allele, as has been presumed [2,3,4]: splicing of residual 59 untranslated and 39 coding sequences can generate an abnormal mRNA that is translated into an aberrant protein predominantly localized in the cytoplasm
Tbx3D1-3/D1-3 homozygotes were rarely recovered in the fetal period: 25% of Tbx3D1-3/D1-3 mutants were dead by e10.5 and 95% were dead by e12.5 (Table 1)
Summary
The transcription factor TBX3 is critical for human development: heterozygotes bearing point, deletion and insertion mutations in TBX3 have ulnar-mammary syndrome (UMS) consisting of congenital limb defects, apocrine and mammary gland hypoplasia, and dental and genital abnormalities [1]. We show that deletion of the T-box encoding region does not inevitably generate a null allele, as has been presumed [2,3,4]: splicing of residual 59 untranslated and 39 coding sequences can generate an abnormal mRNA that is translated into an aberrant protein predominantly localized in the cytoplasm. Homozygotes for this allele have different phenotypes than those observed with a true null allele that produces no mRNA or protein. These findings have important implications for interpreting the phenotypes of other presumed null alleles of Tbx in mice, and when considering the molecular mechanisms of congenital defects in humans with different types of TBX3 mutations
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