title: Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome.
abstract: BACKGROUND
  Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged.
  
  
  METHODS
  We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing.
  
  
  RESULTS
  In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations.
  
  
  CONCLUSIONS
  These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype-phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.
authors.affiliation: Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Marcocci
authors.forename: Vera
authors.initials: V
authors.lastname: Uliana
authors.forename: Mirella
authors.initials: M
authors.lastname: Bruttini
authors.forename: Rosangela
authors.initials: R
authors.lastname: Artuso
authors.forename: Margherita Cirillo
authors.initials: MC
authors.lastname: Silengo
authors.forename: Marlenka
authors.initials: M
authors.lastname: Zerial
authors.forename: Franco
authors.initials: F
authors.lastname: Bergesio
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.forename: Silvana
authors.initials: S
authors.lastname: Savoldi
authors.forename: Marco
authors.initials: M
authors.lastname: Pennesi
authors.forename: Daniela
authors.initials: D
authors.lastname: Giachino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rombolà
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Fogazzi
authors.forename: Cristina
authors.initials: C
authors.lastname: Rosatelli
authors.forename: Ciro Dresch
authors.initials: CD
authors.lastname: Martinhago
authors.forename: Mario
authors.initials: M
authors.lastname: Carmellini
authors.forename: Roberta
authors.initials: R
authors.lastname: Mancini
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Costanzo
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
mesh_terms: D000368:Aged; D024141:Collagen Type IV / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006417:Hematuria / Q000175:diagnosis / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009394:Nephritis, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis
chemical_list: C466620:COL4A4 protein, human; D024141:Collagen Type IV