Novel TBX3 mutation data in families with ulnar-mammary syndrome indicate a genotype-phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects

Abstract

We describe a family affected by Ulnar-Mammary syndrome (UMS) in which typical UMS traits (hypoplasia of the breast and axillary hair, upper limbs and genital defects) are present together with cardiac malformations and pulmonary stenosis. Sequence analysis of TBX3 shows a new heterozygous mutation that causes a frame-shift (Nt.1586-1587-insC) in exon 6, resulting in a truncated ORF. Recently the expression of Tbx3 has been described also in the septal region of the embryonic murine heart. This observation may establish a link between the congenital heart defects and the TBX3 mutation in this family. Combining the TBX3 mutation data in the literature with this novel mutation we find an association between mutations that disrupt the DNA-binding domain and a higher frequency of severe upper limb malformations and teeth defects. A possible explanation is that mutant TBX3 proteins that retain the T-domain, if translated, might be minimally active in promoting/repressing transcription of target genes in the limbs and in other embryonic tissues.