title: COL4A4 gene study of a European population: description of new mutations causing autosomal dominant Alport syndrome.
abstract: BACKGROUND
  Autosomal forms of Alport syndrome represent 20% of all patients (15% recessive and 5% dominant). They are caused by mutations in the COL4A3 and COL4A4 genes, which encode a-3 and a-4 collagen IV chains of the glomerular basement membrane, cochlea and eye. Thin basement membrane nephropathy may affect up to 1% of the population. The pattern of inheritance in the 40% of cases is the same as autosomal dominant Alport syndrome: heterozygous mutations in these genes. The aim of this study is to detect new pathogenic mutations in the COL4A4 gene in the patients previously diagnosed with autosomal Alport syndrome and thin basement membrane nephropathy in our hospital.
  
  
  METHODS
  We conducted a clinical and genetic study in eleven patients belonging to six unrelated families with aforementioned clinical symptoms and a negative study of COL4A3 gene. The molecular study was made by conformation of sensitive gel electrophoresis (CSGE) and direct sequencing of the fragments that show an altered electrophoretic migration pattern.
  
  
  RESULTS
  We found two pathogenic mutations, not yet described: IVS3 + 1G > C is a replacement of Guanine to Cytosine in position +1 of intron 3, in the splicing region, which leads to a pathogenic mutation. c.4267C > T; p.P1423S is a missense mutation, also considered pathogenic. We also found seven new polymorphisms.
  
  
  CONCLUSIONS
  We describe two new pathogenic mutations, responsible for autosomal dominant Alport syndrome. The other families of the study were undiagnosed owing to problems in the method employed and the possibility of mutations in other genes, giving rise to other diseases with similar symptoms.
authors.affiliation: Department of Medicine, Molecular Medicine Unit, University of Salamanca Salamanca, Spain ; Department of Nephrology, Ávila Hospital Ávila, Spain.
authors.forename: Consolación
authors.initials: C
authors.lastname: Rosado
authors.affiliation: Department of Medicine, Molecular Medicine Unit, University of Salamanca Salamanca, Spain ; IBSAL and IBMCC, University of Salamanca, CSIC and SACYL Salamanca, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Bueno
authors.affiliation: Department of Nephrology, Ávila Hospital Ávila, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Felipe
authors.affiliation: Department of Medicine, Molecular Medicine Unit, University of Salamanca Salamanca, Spain ; IBSAL and IBMCC, University of Salamanca, CSIC and SACYL Salamanca, Spain.
authors.forename: Rogelio
authors.initials: R
authors.lastname: González-Sarmiento
keywords: Autosomal alport syndrome; COL4A4 gene; missense; spicing