Hypomorphic PCNA mutation underlies a human DNA repair disorder
Emma L. Baple, … , Catherine M. Green, Andrew H. Crosby
Emma L. Baple, … , Catherine M. Green, Andrew H. Crosby
Published June 9, 2014
Citation Information: J Clin Invest. 2014;124(7):3137-3146. https://doi.org/10.1172/JCI74593.
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Research Article Genetics

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

Emma L. Baple, Helen Chambers, Harold E. Cross, Heather Fawcett, Yuka Nakazawa, Barry A. Chioza, Gaurav V. Harlalka, Sahar Mansour, Ajith Sreekantan-Nair, Michael A. Patton, Martina Muggenthaler, Phillip Rich, Karin Wagner, Roselyn Coblentz, Constance K. Stein, James I. Last, A. Malcolm R. Taylor, Andrew P. Jackson, Tomoo Ogi, Alan R. Lehmann, Catherine M. Green, Andrew H. Crosby

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Figure 1

Family pedigree showing PCNA c.683G>T genotype data and images of affected individuals.

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Family pedigree showing PCNA c.683G>T genotype data and images of aff...
(A) Simplified pedigree of the extended Amish family investigated, with pictorial representation of genotypes across ∼6 Mb of chromosome 20 encompassing the disease locus (dashed blue boxed region, 2.72-Mb autozygous section in affected females; red boxed region, common 0.77-Mb region). Genotype is shown in red under individuals in generations V and VI (+, mutant; –, WT). All affected individuals were subsequently shown to be homozygous for the PCNA variant NM_002592.2 c.683G>T (indicated). Parental samples were heterozygous, and unaffected siblings were either WT or heterozygous carriers. (B) Electropherograms showing the DNA sequence at the position of PCNA c.683G>T in a WT control and a homozygous affected individual. (C–J) Clinical features of individuals homozygous for PCNA c.683G>T. (C and D) Patient VI:6 at 8 (C) and 31 (D) years of age, showing signs of premature aging. (E) Patient VI:7 at 11 years of age, with bilateral hearing aids in situ. (F) Midline sagittal T1-weighted brain scan of patient VI:9 at 8 years of age. Atrophy of the cerebellar vermis resulted in enlargement of vermian sulci and mild widening of the fourth ventricle. The brainstem was normal in appearance, and no supratentorial abnormality was noted. (G and H) Ocular and cutaneous telangiectasia in patients VI:7 and VI:11. (I) Pes cavus in patient VI:11. (J) Photosensitivity after minimal sun exposure in patient VI:11.