Table 1 Genetic diseases associated with TB domain proteins and related pathologies

The main features of each disease are summarized, along with the gene involved and the effect on TGFβ signalling where relevant.

DiseaseSymptomsGene involvedRole of TGFβReferences
Marfan syndromeElongation of the long bonesArachnodactyly (long fingers)Pectus carinatum/ pectus excavatumAbnormal joint flexibilityHigh arched palateEctopia lentis and early onset glaucomaAortic aneurysm and dilatationMitral valve prolapseFBN1 (dominant)Excessive free TGFβ seen in mouse models. Increased levels of phosphorylated Smad2 seen in Marfan syndrome aorta[17,21,37,102]
Shprintzen–Goldberg syndromeCraniosynostosis (early fusion of skull bones)FBN1 (dominant)Unknown[19]
Arachnodactyly (long fingers) and other Marfan-like skeletal features
Mitral valve prolapse may occur, but aortic dilatation rare
Stiff skin syndromeTight and thick skinLimited joint mobilityShort statureFBN1 (dominant)Increase in phosphorylated Smad2 in dermis, indicative of TGFβ signalling[18]
Weill–Marchesani syndromeShort statureFBN1 (dominant)Unknown[20]
Brachydactyly (short fingers)ADAMTS10 (recessive)
Thick skin
Myopia, glaucoma and ectopia lentis
Beals syndromeContractural arachnodactyly (long fingers bent in at the joints) and contractures of various other jointsFBN2 (dominant)Unknown[17,21]
‘Crumpled’ ears
LTBP2 mutationPrimary congenital glaucoma, or secondary glaucoma with megalocornea and spherophakiaLTBP2 (recessive)Unknown[2931]
LTBP3 mutationOligodontia, failure of six or more teeth to developLTBP3 (recessive)Unknown[32]
Short stature
LTBP4 mutationSevere developmental defects in the pulmonary, gastrointestinal, genitourinary, musculoskeletal and dermal systemsLTBP4 (recessive)TGFβ signalling shown to be significantly higher when patient fibroblasts co-cultured with reporter cells[33]
Loeys–Dietz syndromeCleft palate or bifid uvulaAbnormally long limbs and fingersTGFBR1 (dominant)TGFBR2 (dominant)Increased levels of phosphorylated Smad2 in aorta[37,38]
Pectus excavatum
Contractures of fingers and toes
Abnormal joint flexibility
Widely spaced eyes
Aortic aneurysm and aortic dissection with tortuosity