title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
abstract: Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baple
authors.forename: Helen
authors.initials: H
authors.lastname: Chambers
authors.forename: Harold E
authors.initials: HE
authors.lastname: Cross
authors.forename: Heather
authors.initials: H
authors.lastname: Fawcett
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Barry A
authors.initials: BA
authors.lastname: Chioza
authors.forename: Gaurav V
authors.initials: GV
authors.lastname: Harlalka
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Ajith
authors.initials: A
authors.lastname: Sreekantan-Nair
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.forename: Martina
authors.initials: M
authors.lastname: Muggenthaler
authors.forename: Phillip
authors.initials: P
authors.lastname: Rich
authors.forename: Karin
authors.initials: K
authors.lastname: Wagner
authors.forename: Roselyn
authors.initials: R
authors.lastname: Coblentz
authors.forename: Constance K
authors.initials: CK
authors.lastname: Stein
authors.forename: James I
authors.initials: JI
authors.lastname: Last
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Green
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000293:Adolescent; D000328:Adult; D019588:Aging, Premature / Q000235:genetics; D019943:Amino Acid Substitution; D002648:Child; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D004252:DNA Mutational Analysis; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004392:Dwarfism / Q000235:genetics; D005260:Female; D034381:Hearing Loss / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D010787:Photosensitivity Disorders / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013684:Telangiectasis / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins