title: Spectrum of FANCA mutations in Italian Fanconi anemia patients: identification of six novel alleles and phenotypic characterization of the S858R variant.
abstract: Fanconi anemia (FA) is an autosomal recessive disorder characterized by genomic instability, bone marrow failure, congenital malformations, and cancer predisposition. FA is a genetically heterogeneous disease with at least seven genes so far identified. The role of FA proteins is unknown although they interact in a common functional pathway. Here, we report six novel FANCA sequence changes and review all the mutations identified in Italy. Except for two missense substitutions, all are expected to cause a premature termination of the FANCA protein at various sites throughout the molecule. The premature terminations are due to nonsense and splice site mutations, as well as small insertions and deletions, and large genomic rearrangements. The expected truncated proteins were not detectable on Western blot analyses. The FANCA-S858R variant is instead expressed at lower level than that seen in normal cell lines and is associated with a non-ubiquinated FANCD2 protein, strongly suggesting that the amino acid substitution is a disease-causing mutation. The spectrum of FA mutations is widely in agreement with the heterogeneous ethnic origin of the Italian population.
authors.affiliation: Servizio di Genetica Medica, IRCCS-Ospedale CSS, San Giovanni Rotondo, Foggia, Italy. savoia@tigen.it
authors.forename: Maria
authors.initials: M
authors.lastname: Savino
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.forename: Maria
authors.initials: M
authors.lastname: D'Apolito
authors.forename: Maria
authors.initials: M
authors.lastname: Criscuolo
authors.forename: Maria
authors.initials: M
authors.lastname: Del Vecchio
authors.forename: Anna Monica
authors.initials: AM
authors.lastname: Bianco
authors.forename: Michele
authors.initials: M
authors.lastname: Di Perna
authors.forename: Rita
authors.initials: R
authors.lastname: Calzone
authors.forename: Bruno
authors.initials: B
authors.lastname: Nobili
authors.forename: Adriana
authors.initials: A
authors.lastname: Zatterale
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Zelante
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D015153:Blotting, Western; D002460:Cell Line; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein; D006801:Humans; D007558:Italy; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing
chemical_list: D004268:DNA-Binding Proteins; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D011506:Proteins