Spectrum of FANCA mutations in Italian Fanconi anemia patients: identification of six novel alleles and phenotypic characterization of the S858R variant.
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.
Savino
Maria
M
Servizio di Genetica Medica, IRCCS-Ospedale CSS, San Giovanni Rotondo, Foggia, Italy. savoia@tigen.it
Borriello
Adriana
A
D'Apolito
Maria
M
Criscuolo
Maria
M
Del Vecchio
Maria
M
Bianco
Anna Monica
AM
Di Perna
Michele
M
Calzone
Rita
R
Nobili
Bruno
B
Zatterale
Adriana
A
Zelante
Leopoldo
L
Joenje
Hans
H
Della Ragione
Fulvio
F
Savoia
Anna
A
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
D004268:DNA-Binding Proteins; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D011506:Proteins