| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
From the Saul R. Korey Department of Neurology (Drs. Rapin, Lindenbaum, and Dickson), the Department of Pediatrics (Dr. Rapin), the Rose F. Kennedy Center for Research in Mental Retardation and Human Development (Drs. Rapin and Dickson), and the Division of Neuropathology (Dr. Dickson), Department of Pathology, Albert Einstein College of Medicine, Bronx, NY; the Department of Neurology (Dr. Lindenbaum), Ohio State University College of Medicine, Columbus; the Department of Pathology (Dr. Dickson), Mayo Clinic Jacksonville, FL; the Basic Research Laboratory (Dr. Kraemer) and the Dermatology Branch (Dr. Robbins), National Cancer Institute, NIH, Bethesda, MD.
Address correspondence and reprint requests to Dr. Isabelle Rapin, Room 807 Kennedy Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461; e-mail: rapin{at}aecom.yu.edu
OBJECTIVES: To review genetic variants of Cockayne syndrome (CS) and xeroderma pigmentosum (XP), autosomal recessive disorders of DNA repair that affect the nervous system, and to illustrate them by the first case of xeroderma pigmentosum–Cockayne syndrome (XP-CS) complex to undergo neuropathologic examination.
METHODS: Published reports of clinical, pathologic, and molecular studies of CS, XP neurologic disease, and the XP-CS complex were reviewed, and a ninth case of XP-CS is summarized.
RESULTS: CS is a multisystem disorder that causes both profound growth failure of the soma and brain and progressive cachexia, retinal, cochlear, and neurologic degeneration, with a leukodystrophy and demyelinating neuropathy without an increase in cancer. XP presents as extreme photosensitivity of the skin and eyes with a 1000-fold increased frequency of cutaneous basal and squamous cell carcinomas and melanomas and a small increase in nervous system neoplasms. Some 20% of patients with XP incur progressive degeneration of previously normally developed neurons resulting in cortical, basal ganglia, cerebellar, and spinal atrophy, cochlear degeneration, and a mixed distal axonal neuropathy. Cultured cells from patients with CS or XP are hypersensitive to killing by ultraviolet (UV) radiation. Both CS and most XP cells have defective DNA nucleotide excision repair of actively transcribing genes; in addition, XP cells have defective repair of the global genome. There are two complementation groups in CS and seven in XP. Patients with the XP-CS complex fall into three XP complementation groups. Despite their XP genotype, six of nine individuals with the XP-CS complex, including the boy we followed up to his death at age 6, had the typical clinically and pathologically severe CS phenotype. Cultured skin and blood cells had extreme sensitivity to killing by UV radiation, DNA repair was severely deficient, post-UV unscheduled DNA synthesis was reduced to less than 5%, and post-UV plasmid mutation frequency was increased.
CONCLUSIONS: The paradoxical lack of parallelism of phenotype to genotype is unexplained in these disorders. Perhaps diverse mutations responsible for UV sensitivity and deficient DNA repair may also produce profound failure of brain and somatic growth, progressive cachexia and premature aging, and tissue-selective neurologic deterioration by their roles in regulation of transcription and repair of endogenous oxidative DNA damage.–1449
This article has been cited by other articles:
|
|
 |
|
  M. Muftuoglu, N. C. de Souza-Pinto, A. Dogan, M. Aamann, T. Stevnsner, I. Rybanska, G. Kirkali, M. Dizdaroglu, and V. A. Bohr Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase J. Biol. Chem., April 3, 2009; 284(14): 9270 - 9279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Faghri, D Tamura, K H Kraemer, and J J DiGiovanna Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations J. Med. Genet., October 1, 2008; 45(10): 609 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V Laugel, C Dalloz, E S Tobias, J L Tolmie, D Martin-Coignard, V Drouin-Garraud, V Valayannopoulos, A Sarasin, and H Dollfus Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation J. Med. Genet., September 1, 2008; 45(9): 564 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Anttinen, L. Koulu, E. Nikoskelainen, R. Portin, T. Kurki, M. Erkinjuntti, N. G. J. Jaspers, A. Raams, M. H. L. Green, A. R. Lehmann, et al. Neurological symptoms and natural course of xeroderma pigmentosum Brain, August 1, 2008; 131(8): 1979 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Pavelitz, A. D. Bailey, C. P. Elco, and A. M. Weiner Human U2 snRNA Genes Exhibit a Persistently Open Transcriptional State and Promoter Disassembly at Metaphase Mol. Cell. Biol., June 1, 2008; 28(11): 3573 - 3588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sugasawa Xeroderma pigmentosum genes: functions inside and outside DNA repair Carcinogenesis, March 1, 2008; 29(3): 455 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Thyagarajan, K. E. Anderson, C. J. Lessard, G. Veltri, D. R. Jacobs, A. R. Folsom, and M. D. Gross Alkaline unwinding flow cytometry assay to measure nucleotide excision repair Mutagenesis, March 1, 2007; 22(2): 147 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Mizuki, T. Namiki, H. Sato, H. Furukawa, T. Matsusaka, Y. Ohshima, R. Ishibashi, T. Andoh, and T. Tani Participation of XPB/Ptr8p, a component of TFIIH, in nucleocytoplasmic transport of mRNA in fission yeast. Genes Cells, January 1, 2007; 12(1): 35 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Newman, A. D. Bailey, and A. M. Weiner Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling PNAS, June 20, 2006; 103(25): 9613 - 9618. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Sonmez, F. Celep, and S. A. Ugur Severe Form of Cockayne Syndrome With Varying Clinical Presentation and No Photosensitivity in a Family J Child Neurol, April 1, 2006; 21(4): 333 - 337. [Abstract] [PDF]
|
|
|
|
|
|
S. G. Khan, K.-S. Oh, T. Shahlavi, T. Ueda, D. B. Busch, H. Inui, S. Emmert, K. Imoto, V. Muniz-Medina, C. C. Baker, et al. Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients Carcinogenesis, January 1, 2006; 27(1): 84 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D'Arrigo, L. Vigano, M. G. Bruzzone, M. Marzaroli, I. Nikas, D. Riva, and C. Pantaleoni Diagnostic Approach to Cerebellar Disease in Children J Child Neurol, November 1, 2005; 20(11): 859 - 866. [Abstract] [PDF]
|
|
|
|
 |
|
 Y. Baba, D. F. Broderick, R. J. Uitti, M. L. Hutton, and Z. K. Wszolek Heredofamilial Brain Calcinosis Syndrome Mayo Clin. Proc., May 1, 2005; 80(5): 641 - 651. [Abstract] [PDF]
|
|
|
|
|
|
H. Luo, D. W. Chan, T. Yang, M. Rodriguez, B. P.-C. Chen, M. Leng, J.-J. Mu, D. Chen, Z. Songyang, Y. Wang, et al. A New XRCC1-Containing Complex and Its Role in Cellular Survival of Methyl Methanesulfonate Treatment Mol. Cell. Biol., October 1, 2004; 24(19): 8356 - 8365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. de Waard, J. de Wit, J.-O. Andressoo, C. T. M. van Oostrom, B. Riis, A. Weimann, H. E. Poulsen, H. van Steeg, J. H. J. Hoeijmakers, and G. T. J. van der Horst Different Effects of CSA and CSB Deficiency on Sensitivity to Oxidative DNA Damage Mol. Cell. Biol., September 15, 2004; 24(18): 7941 - 7948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Perlow, T. M. Schinecker, S. J. Kim, N. E. Geacintov, and D. A. Scicchitano Construction and purification of site-specifically modified DNA templates for transcription assays Nucleic Acids Res., April 1, 2003; 31(7): e40 - e40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. TUO, P. JARUGA, H. RODRIGUEZ, V. A. BOHR, and M. DIZDAROGLU Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress FASEB J, April 1, 2003; 17(6): 668 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Broughton, M. Berneburg, H. Fawcett, E. M. Taylor, C. F. Arlett, T. Nardo, M. Stefanini, E. Menefee, V. H. Price, S. Queille, et al. Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene Hum. Mol. Genet., October 1, 2001; 10(22): 2539 - 2547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Emmert, T. D. Schneider, S. G. Khan, and K. H. Kraemer The human XPG gene: gene architecture, alternative splicing and single nucleotide polymorphisms Nucleic Acids Res., April 1, 2001; 29(7): 1443 - 1452. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
