Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome

Am J Hum Genet. 2002 Jul;71(1):30-44. doi: 10.1086/341035. Epub 2002 May 6.


To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aortic Stenosis, Supravalvular / genetics*
  • Aortic Stenosis, Supravalvular / metabolism
  • Aortic Stenosis, Supravalvular / pathology*
  • Base Sequence
  • Case-Control Studies
  • Cell Division / genetics
  • Cell Division / physiology
  • Cells, Cultured
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA, Complementary / genetics
  • Elastin / deficiency*
  • Elastin / genetics*
  • Elastin / metabolism
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Solubility
  • Williams Syndrome / genetics*
  • Williams Syndrome / metabolism
  • Williams Syndrome / pathology*


  • DNA, Complementary
  • RNA, Messenger
  • Elastin

Associated data

  • OMIM/185500
  • OMIM/194050