Nature Genetics
22, 379 - 383 (1999)
doi:10.1038/11956
Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicismQuinten Waisfisz1, Neil V. Morgan2, Maria Savino3, Johan P. de Winter1, Carola G.M. van Berkel1, Maureen E. Hoatlin4, Leonarda Ianzano3, Rachel A. Gibson2, Fre Arwert1, Anna Savoia3, Christopher G. Mathew2, Jan C. Pronk1
& Hans Joenje11
Department of Clinical Genetics and Human Genetics, Free University, Van der Boechorststraat 7, NL-1081 BT, Amsterdam, The Netherlands. 2
Division of Medical and Molecular Genetics UMDS, Guy's Hospital, King's and St. Thomas' School of Medicine, London SE1 9RT, UK. 3
Servizio di Genetica Medica, IRCCS-Ospedale CSS, I-71013 San Giovanni Rotondo, Foggia, Italy. 4
Division of Hematology and Medical Oncology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, Oregon 97201, USA.
Correspondence should be addressed to Hans Joenje H.Joenje.HumGen@med.vu.nlSomatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders1,
2,
3,
4,
5,
6. 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 anaemia7 (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 1748CT, 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.
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