Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF
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...
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doaj-93c4b2d6ae9b43e6ab30e0d0bb56dc552021-04-02T17:23:39ZengBMCBMC Medical Genetics1471-23502018-01-0119111010.1186/s12881-018-0520-1Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPFIsabell Popp0Maqsood Punekar1Nick Telford2Stavros Stivaros3Kate Chandler4Meenakshi Minnis5Anna Castleton6Claire Higham7Louise Hopewell8D. Gareth Evans9Anja Raams10Arjan F. Theil11Stefan Meyer12Detlev Schindler13Department of Human Genetics, Biozentrum, University of WurzburgLancashire Teaching Hospitals NHS Foundation TrustOncology Cytogenetics, The Christie NHS Foundation TrustInstitute of Population Health, Centre for Imaging Sciences, Faculty of Medical and Human Sciences, University of ManchesterManchester Academic Health Science CentreManchester Academic Health Science CentreDepartment of Paediatric and Adolescent Oncology, The Christie NHS Foundation TrustDepartment of Paediatric and Adolescent Oncology, The Christie NHS Foundation TrustDepartment of Paediatric and Adolescent Oncology, The Christie NHS Foundation TrustDepartment of Genetic Medicine, St Mary’s Hospital, Central Manchester Foundation TrustDepartment of Molecular Genetics, Erasmus Medical CenterDepartment of Molecular Genetics, Erasmus Medical CenterManchester Academic Health Science CentreDepartment of Human Genetics, Biozentrum, University of WurzburgAbstract 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.http://link.springer.com/article/10.1186/s12881-018-0520-1Fanconi anemiaUV sensitivityXPFERCC4FANCQDNA repair |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Isabell Popp Maqsood Punekar Nick Telford Stavros Stivaros Kate Chandler Meenakshi Minnis Anna Castleton Claire Higham Louise Hopewell D. Gareth Evans Anja Raams Arjan F. Theil Stefan Meyer Detlev Schindler |
spellingShingle |
Isabell Popp Maqsood Punekar Nick Telford Stavros Stivaros Kate Chandler Meenakshi Minnis Anna Castleton Claire Higham Louise Hopewell D. Gareth Evans Anja Raams Arjan F. Theil Stefan Meyer Detlev Schindler Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF BMC Medical Genetics Fanconi anemia UV sensitivity XPF ERCC4 FANCQ DNA repair |
author_facet |
Isabell Popp Maqsood Punekar Nick Telford Stavros Stivaros Kate Chandler Meenakshi Minnis Anna Castleton Claire Higham Louise Hopewell D. Gareth Evans Anja Raams Arjan F. Theil Stefan Meyer Detlev Schindler |
author_sort |
Isabell Popp |
title |
Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF |
title_short |
Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF |
title_full |
Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF |
title_fullStr |
Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF |
title_full_unstemmed |
Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF |
title_sort |
fanconi anemia with sun-sensitivity caused by a xeroderma pigmentosum-associated missense mutation in xpf |
publisher |
BMC |
series |
BMC Medical Genetics |
issn |
1471-2350 |
publishDate |
2018-01-01 |
description |
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. |
topic |
Fanconi anemia UV sensitivity XPF ERCC4 FANCQ DNA repair |
url |
http://link.springer.com/article/10.1186/s12881-018-0520-1 |
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