title: Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.
abstract: Somatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders. The best known mechanism involves intragenic mitotic recombination or gene conversion in compound heterozygous patients, whereby one allele serves to restore the wild-type sequence in the other. Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia (FA) patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC(1749T-->G, Leu496Arg) was altered by 1748C-->T, creating a cysteine codon. Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type.
authors.affiliation: Department of Clinical Genetics and Human Genetics, Free University, Amsterdam, The Netherlands.
authors.forename: Q
authors.initials: Q
authors.lastname: Waisfisz
authors.forename: N V
authors.initials: NV
authors.lastname: Morgan
authors.forename: M
authors.initials: M
authors.lastname: Savino
authors.forename: J P
authors.initials: JP
authors.lastname: de Winter
authors.forename: C G
authors.initials: CG
authors.lastname: van Berkel
authors.forename: M E
authors.initials: ME
authors.lastname: Hoatlin
authors.forename: L
authors.initials: L
authors.lastname: Ianzano
authors.forename: R A
authors.initials: RA
authors.lastname: Gibson
authors.forename: F
authors.initials: F
authors.lastname: Arwert
authors.forename: A
authors.initials: A
authors.lastname: Savoia
authors.forename: C G
authors.initials: CG
authors.lastname: Mathew
authors.forename: J C
authors.initials: JC
authors.lastname: Pronk
authors.forename: H
authors.initials: H
authors.lastname: Joenje
mesh_terms: D000483:Alleles; D001483:Base Sequence; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005199:Fanconi Anemia / Q000235:genetics*; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D008297:Male; D008745:Methylation; D008969:Molecular Sequence Data; D009030:Mosaicism; D009687:Nuclear Proteins; D010641:Phenotype; D011233:Precipitin Tests; D011506:Proteins / Q000235:genetics; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C497651:FANCC protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins