title: X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.
abstract: Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.
authors.affiliation: Biostatistique et Informatique Médicale, U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Jais
authors.affiliation: Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Knebelmann
authors.affiliation: Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Iannis
authors.initials: I
authors.lastname: Giatras
authors.affiliation: The Italian Multicenter Study on Alport Syndrome, Italy.
authors.forename: Mario DE
authors.initials: M
authors.lastname: Marchi
authors.affiliation: The Italian Multicenter Study on Alport Syndrome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Rizzoni
authors.affiliation: The Italian Multicenter Study on Alport Syndrome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Hospital Köln Merheim, Cologne, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Weber
authors.affiliation: Hospital Köln Merheim, Cologne, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
authors.affiliation: Hospital Köln Merheim, Cologne, Germany.
authors.forename: Kai-Olaf
authors.initials: KO
authors.lastname: Netzer
authors.affiliation: Guy's Hospital, University of London, United Kingdom.
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.affiliation: Université Catholique de Louvain, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pirson
authors.affiliation: Université Catholique de Louvain, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Verellen
authors.affiliation: University Hospital, Lund, Sweden.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Wieslander
authors.affiliation: University Hospital, Lund, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Persson
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Paula
authors.initials: P
authors.lastname: Martin
authors.affiliation: Aarhus University Hospital, Denmark.
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Hertz
authors.affiliation: University Hospital of Nijmegen, The Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Schröder
authors.affiliation: Jagiellonian University Medical School, Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Sanak
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Krejcova
authors.affiliation: Curry Cabral Hospital, Lisbonne, Portugal.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Carvalho
authors.affiliation: Fundación Valenciana de Investigaciones Biomédicas, Instituto de Investigaciones Citológicas, Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Saus
authors.affiliation: Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.affiliation: University of Maastricht, The Netherlands.
authors.forename: Hubert
authors.initials: H
authors.lastname: Smeets
authors.affiliation: Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Marie Claire
authors.initials: MC
authors.lastname: Gubler
mesh_terms: D000328:Adult; D001485:Basement Membrane / Q000378:metabolism / Q000648:ultrastructure; D003094:Collagen / Q000235:genetics; D003638:Deafness / Q000150:complications / Q000453:epidemiology; D018450:Disease Progression; D005128:Eye Diseases / Q000150:complications / Q000453:epidemiology; D015321:Gene Rearrangement; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic; D007678:Kidney Glomerulus / Q000378:metabolism / Q000648:ultrastructure; D016030:Kidney Transplantation; D008297:Male; D009154:Mutation / Q000235:genetics; D009394:Nephritis, Hereditary / Q000150:complications / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D010641:Phenotype; D014960:X Chromosome
chemical_list: D003094:Collagen