Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

Hum Mol Genet. 2015 Jun 1;24(11):3038-49. doi: 10.1093/hmg/ddv053. Epub 2015 Feb 10.


Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amelogenesis Imperfecta / diagnostic imaging
  • Amelogenesis Imperfecta / genetics*
  • Animals
  • Base Sequence
  • Child
  • Consanguinity
  • DNA Mutational Analysis
  • Female
  • Frameshift Mutation
  • Genetic Association Studies
  • Humans
  • Latent TGF-beta Binding Proteins / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation, Missense
  • Osteochondrodysplasias / diagnostic imaging
  • Osteochondrodysplasias / genetics*
  • Pedigree
  • Radiography
  • Sequence Deletion


  • LTBP3 protein, human
  • Latent TGF-beta Binding Proteins

Supplementary concepts

  • Brachyolmia