Molecular characteristics

The majority of the LDS3-causing SMAD3 mutations consist of missense mutations (61%), frameshift mutations (23%), nonsense mutations (7%) and mutations that affect a splice site (6%). Because of the frequent occurrence of truncating mutations, SMAD3 mutations are predicted to lead to loss of function of the encoded protein. Despite this, a paradoxical gain-of-function on the overall TGFβ signaling pathway has been observed. SMAD3 is an intracellular downstream effector of the TGFβ pathway. The majority of the SMAD3 mutations reside in the MH2 domain, a well conserved region responsible for the oligomerization of SMAD2 or SMAD3 with SMAD4 and subsequent SMAD-dependent activation of downstream transcription.

Currently, molecular diagnostics in LDS patients most typically involves gene panel sequencing or exome sequencing.

Somatic SMAD3-activating mutations are shown to lead to melorheostosis.