Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism

Quinten Waisfisz, Neil V. Morgan, Maria Savino, Johan P. De Winter, Carola G.M. Van Berkel, Maureen E. Hoatlin, Leonarda Ianzano, Rachel A. Gibson, Fre Arwert, Anna Savoia, Christopher G. Mathew, Jan C. Pronk, Hans Joenje*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 1641deIT); 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.

Original languageEnglish
Pages (from-to)379-383
Number of pages5
JournalNature Genetics
Issue number4
Publication statusPublished - Aug 1999

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