title: Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene.
abstract: BACKGROUND
  Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown.
  
  
  METHODS
  Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation.
  
  
  RESULTS
  Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic.
  
  
  CONCLUSIONS
  This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.
authors.affiliation: Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pescucci
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Vogiatzi
authors.forename: Rossella
authors.initials: R
authors.lastname: Caselli
authors.forename: Elisa
authors.initials: E
authors.lastname: Scala
authors.forename: Cataldo
authors.initials: C
authors.lastname: Abaterusso
authors.forename: Rosanna
authors.initials: R
authors.lastname: Gusmano
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Nunzia
authors.initials: N
authors.lastname: Miglietti
authors.forename: Elena
authors.initials: E
authors.lastname: Bresin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000235:genetics*; D002648:Child; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain