1. Hypomorphic PCNA mutation underlies a human DNA repair disorder.
- Author
-
Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, and Crosby AH
- Subjects
- Adolescent, Adult, Aging, Premature genetics, Amino Acid Substitution, Child, Chromosomes, Human, Pair 20 genetics, DNA Mutational Analysis, DNA Repair-Deficiency Disorders pathology, DNA Repair-Deficiency Disorders physiopathology, Dwarfism genetics, Female, Hearing Loss genetics, Homozygote, Humans, Male, Models, Molecular, Mutant Proteins chemistry, Mutant Proteins metabolism, Nerve Degeneration genetics, Pedigree, Phenotype, Photosensitivity Disorders genetics, Proliferating Cell Nuclear Antigen chemistry, Proliferating Cell Nuclear Antigen metabolism, Protein Structure, Quaternary, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Syndrome, Telangiectasis genetics, DNA Repair-Deficiency Disorders genetics, Mutant Proteins genetics, Mutation, Missense, Proliferating Cell Nuclear Antigen genetics
- 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.
- Published
- 2014
- Full Text
- View/download PDF