Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF

Abstract

BackgroundFanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks.Case presentationA fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient’s cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus.ConclusionsPatients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0520-1) contains supplementary material, which is available to authorized users.

Heterogeneity and overlaps in nucleotide excision repair disorders

“…The second set of ERCC4 variants results in the nuclear localization of the mutated proteins that exert a sufficient, although not optimal, NER activity but are fully deficient in ICLs repair. These mutations result in the FA phenotype . The last category of ERCC4 variants is characterized by very low levels of nuclear XPF, apparently insufficient to support either NER or ICLs repair.…”

“…These mutations result in the FA phenotype. 15,16 The last category of ERCC4 variants is characterized by very low levels of nuclear XPF, apparently insufficient to support either NER or ICLs repair. These mutations are associated with severe CS, XFE and combined presentations.…”

“…FA is a myelodysplastic disorder characterized by progressive bone marrow failure and blood cancer predisposition resulting from defective repair of DNA inter‐strand crosslinks (ICLs). Of note, partial NER deficiency has been found in few FA cases …”

“…Of note, partial NER deficiency has been found in few FA cases. 15,16 The remarkable phenotypic complexity of NER disorders is underlined by an intricate genetic scenario. Twelve NER genes have been associated to five distinct disorders and five different combined phenotypes.…”

A Homozygous Missense Mutation in <b><i>FANCA</i></b> Gene in a 46,XY Female with Gonadal Dysgenesis

“…To date, at least 22 different genes are associated with FA [Popp et al, 2018]. The products of these genes are involved in DNA damage repair and oxidative stress mechanisms [Pagano and Zatterale, 2015] .…”