TBX3 – Ulnar-Mammary Syndrome

Ulnar-mammary syndrome (UMS) is a rare autosomal dominant disorder characterized by posterior limb deficiencies, mammary gland hypoplasia, apocrine dysfunction, dental anomalies, and genital abnormalities (PMID:9207801). Mutations in TBX3 (HGNC:11602) underlie UMS (MONDO:0008411) via haploinsufficiency, as first demonstrated in two families and subsequently confirmed across diverse populations.

Clinically, UMS shows high intrafamilial variability. Segregation analysis in a large Turkish pedigree identified 10 affected individuals over three generations (PMID:12668170) and a Japanese family contributed 3 additional cases (PMID:12116211). Across at least seven unrelated kindreds, 19 relatives co-segregate TBX3 variants with UMS phenotypes, substantiating dominant inheritance.

Genetic studies have uncovered a spectrum of heterozygous TBX3 variants, including nonsense, frameshift, splice-site, and deep-intronic mutations. Notable examples are c.817A>T (p.Lys273Ter) in exon 4 (PMID:12116211) and c.657+1G>C affecting the splice donor (PMID:9207801). These variants truncate the C-terminal repression domain, abolishing transcriptional regulatory activity.

Functional assays consistently support haploinsufficiency as the pathogenic mechanism. TBX3 binds and represses target promoters via its C-terminal repression domain; mutants lacking this domain exhibit reduced DNA binding and failed transcriptional repression (PMID:10468588, PMID:11689487). Mouse models with hypomorphic or null alleles phenocopy human conduction defects and limb malformations, confirming dosage sensitivity.

No studies to date have refuted the TBX3–UMS association. Reports of contiguous deletions involving TBX5 and TBX3 underscore phenotypic overlap with Holt-Oram syndrome but do not dispute TBX3’s role in UMS alone.

In summary, definitive evidence from multi-generation pedigrees, diverse variant types, and convergent functional data establishes TBX3 haploinsufficiency as the cause of UMS. TBX3 genetic testing is clinically useful for diagnosis, family counseling, and guiding surveillance for endocrine and cardiac features.

Key Take-home: TBX3 mutation analysis should be pursued in patients with ulnar-ray defects and mammary or genital anomalies to confirm UMS and inform management.

References

• Annales de genetique • 2002 • Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. PMID:12668170
• American journal of medical genetics • 2002 • Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. PMID:12116211
• Nature genetics • 1997 • Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. PMID:9207801
• American journal of human genetics • 1999 • The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome. PMID:10330342
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. PMID:10468588
• Human molecular genetics • 2001 • A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. PMID:11689487

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