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BMC Med Genet. 2018 Jan 11;19(1):7. doi: 10.1186/s12881-018-0520-1.

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

Author information

1
Department of Human Genetics, Biozentrum, University of Wurzburg, Am Hubland, 97074, Wurzburg, Germany.
2
Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.
3
Oncology Cytogenetics, The Christie NHS Foundation Trust, Manchester, UK.
4
Institute of Population Health, Centre for Imaging Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
5
Manchester Academic Health Science Centre, Manchester, UK.
6
Department of Genetic Medicine, St Mary's Hospital, Central Manchester Foundation Trust, Manchester, UK.
7
Department of Paediatric and Adolescent Oncology, The Christie NHS Foundation Trust, Manchester, UK.
8
Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
9
Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
10
Manchester Academic Health Science Centre, Manchester, UK. stefan.meyer@manchester.ac.uk.
11
Department of Paediatric and Adolescent Oncology, The Christie NHS Foundation Trust, Manchester, UK. stefan.meyer@manchester.ac.uk.
12
Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. stefan.meyer@manchester.ac.uk.
13
Department of Paediatric and Adolescent Oncology, Royal Manchester Children's Hospital, Manchester, UK. stefan.meyer@manchester.ac.uk.
14
Paediatric and Adolescent Oncology, Division of Cancer Sciences, University of Manchester, c/o Young Oncology Unit, Christie Hospital, Wilmslow Road, Manchester, M20 6XB, UK. stefan.meyer@manchester.ac.uk.
15
Department of Human Genetics, Biozentrum, University of Wurzburg, Am Hubland, 97074, Wurzburg, Germany. schindler@biozentrum.uni-wuerzburg.de.

Abstract

BACKGROUND:

Fanconi 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 PRESENTATION:

A 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.

CONCLUSIONS:

Patients 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.

KEYWORDS:

DNA repair; ERCC4; FANCQ; Fanconi anemia; UV sensitivity; XPF

PMID:
29325523
PMCID:
PMC5765604
DOI:
10.1186/s12881-018-0520-1
[Indexed for MEDLINE]
Free PMC Article

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