Missense variations in the fibulin 5 gene and age-related macular degeneration

N Engl J Med. 2004 Jul 22;351(4):346-53. doi: 10.1056/NEJMoa040833.

Abstract

Background: Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world. The study of a rare mendelian form of macular degeneration implicated fibulin genes in the pathogenesis of more common forms of this disease. We evaluated five fibulin genes in a large series of patients with AMD.

Methods: We studied 402 patients with AMD and 429 control subjects from the same clinic population. Patients were examined by means of indirect ophthalmoscopy, slit-lamp microscopy, and fundus photography to establish the presence and phenotypic pattern of AMD. DNA samples were screened for sequence variations in five members of the fibulin gene family.

Results: Amino acid-altering sequence variations were found in all five fibulin genes, many of which were observed only in patients with AMD. Several of the altered residues have been conserved during evolution. Seven of the 402 patients with AMD had amino acid-altering sequence variations in the fibulin 5 gene, whereas none were observed among 429 control subjects (P<0.01). In addition, these seven patients all had small, circular drusen, which are commonly referred to as basal laminar or cuticular drusen.

Conclusions: Missense mutations in the fibulin 5 gene were found in 1.7 percent of patients with AMD. Many variations in other fibulin genes were also found in these patients, and the evolutionary conservation of the affected residues suggests that several of these variations may also be involved in AMD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Substitution
  • Calcium-Binding Proteins / genetics
  • Case-Control Studies
  • Cysteine Endopeptidases / genetics
  • DNA Mutational Analysis
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Humans
  • Immunoglobulins / genetics
  • Macular Degeneration / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Recombinant Proteins / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • FBLN5 protein, human
  • HMCN1 protein, human
  • Immunoglobulins
  • Recombinant Proteins
  • fibulin
  • fibulin 2
  • fibulin-4
  • Cysteine Endopeptidases