Disease-associated mutations in conserved residues of ALK-1 kinase domain

Eur J Hum Genet. 2003 Apr;11(4):279-87. doi: 10.1038/sj.ejhg.5200919.


Activin receptor-like kinase-1 (ALK-1), the gene mutated in HHT type 2 (HHT2), is a serine/threonine kinase receptor type I of the TGF-beta superfamily, specifically expressed on endothelial cells. We established an HHT2 genotype in 16 families and report nine novel mutations. These include insertions and deletions of single base pairs in exons 3, 8 and 9, as well as nonsense mutations in exons 4 and 8 of ALK-1, which would lead to premature truncation and unstable mRNA or protein. Three novel missense mutations were identified in exons 7 and 8 of the kinase domain. Five previously reported substitutions were also observed in the families analyzed. Our results bring to 36, the number of mutations associated with HHT2, and are mostly found in exons 8 and 3 followed by exons 4 and 7. To ascertain the potential functional implications of the missense mutations in the ALK-1 kinase domain, we generated a model based on the three-dimensional structure of the homologous ALK-5 kinase domain. Our data reveal that the 11 missense mutations modify residues conserved among type I receptors and alter the polarity, charge, hydrophobicity and/or size of the substituted amino-acid and likely lead to misfolded and nonfunctional proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics*
  • Activin Receptors, Type II
  • Adult
  • Aged
  • Amino Acid Sequence
  • DNA Mutational Analysis
  • Endothelium, Vascular / chemistry
  • Humans
  • Infant, Newborn
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Protein Conformation
  • Sequence Alignment
  • Telangiectasia, Hereditary Hemorrhagic / genetics*


  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II