Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome

Abstract

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Refinement of the RP17 locus for autosomal dominant retinitis pigmentosa, construction of a YAC contig and investigation of the candidate gene retinal fascin

“…The transcriptional regulator TBX2 has been mapped to a YAC from this contig, clone 961f1 12 and exhibits strong sequence homology, within the T-box domain, to the Drosophila optomotor blind (omb) gene. 13 Mutations in two other T-box genes TBX5 and TBX3 have been shown to be responsible for Holt-Oram syndrome 14 and ulnar-mammary syndrome, 15 respectively.…”

Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation

“…Tbx3 is related to Brachyury and other Tbx family members by their shared DNA-binding motif known as the T-domain. Some mutations in Tbx3 that cause UMS disrupt the T-domain and are thought to function as null alleles (Bamshad et al, 1997), but others occur downstream from the Tdomain and may a ect the transcriptional repression activity or other functions of Tbx3 He et al, 1999;Carlson et al, 2001). The range and nature of defects associated with UMS, together with sites of Tbx3 expression Gibson-Brown et al, 1998) are consistent with a key role of Tbx3 as a mediator of regional mesoderm induction and di erentiation.…”

“…Ulnar-mammary syndrome (UMS), caused by heterozygous mutations in Tbx3 (Bamshad et al, 1997, is an autosomal dominant disorder characterized by de®ciencies and duplications of posterior elements of the forelimb, by mammary hypoplasia and apocrine gland de®ciency/dysfunction and by tooth, hair and sex organ defects. Tbx3 is related to Brachyury and other Tbx family members by their shared DNA-binding motif known as the T-domain.…”

“…Although mutations in Brachyury have not been linked to any human disease or birth defects, mutations in a number of other Tbx genes have. These include Tbx1 (DiGeorge syndrome, see Schinke and Izumo (2001) for review), Tbx3 (ulnar-mammary syndrome, Bamshad et al, 1997), Tbx5 (Holt-Oram syndrome, Basson et al, 1997;Li et al, 1997) and Tbx22 (X-linked cleft palate and ankyloglossia, Braybrook et al, 2001). Consistent with known functions of Brachyury, a common theme amongst the human disease syndromes caused by mutations in Tbx family genes is the disruption of regional epithelial/mesodermal interactions and associated defects in mesoderm induction and di erentiation events.…”

X-linked recessive inheritance of radial ray deficiencies in a family with four affected males

“…14,15 Haploinsufficiency of this gene causes mainly anterior limb malformations in patients with Holt-Oram syndrome, whereas haploinsufficiency of the TBX3 gene causes mainly posterior limb malformations in patients with the ulnar-mammary syndrome. 14,16 The gene defect could also be involved in differentiation or growth of the radius. Disturbance of the chondrofication process could result in a fibrous radius; 17,18 disturbance of the ossification process in a cartilagenous one.…”