title: A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.
abstract: Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2), and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids). Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Byrd
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Smith
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Eaton
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Taylor
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Chloe
authors.initials: C
authors.lastname: Guy
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ieva
authors.initials: I
authors.lastname: Eringyte
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Peggy
authors.initials: P
authors.lastname: Fooks
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: James I
authors.initials: JI
authors.lastname: Last
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Horsley
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.affiliation: University Children's Hospital, School of Medicine University of Belgrade, Belgrade, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Janic
authors.affiliation: University Children's Hospital, School of Medicine University of Belgrade, Belgrade, Serbia.
authors.forename: Lidija
authors.initials: L
authors.lastname: Dokmanovic
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
mesh_terms: D000483:Alleles; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D002875:Chromosomes / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D000076164:Fanconi Anemia Complementation Group N Protein; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D051135:Rad51 Recombinase / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D051135:Rad51 Recombinase