Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects

We report that a subject with Cockayne syndrome type A (CS3BE) was a compound heterozygote for mutations in CKN1, the gene encoding the CSA protein (MIM 216400). CS3BE displayed a novel missense mutation (A160V) and a previously described nonsense mutation (E13X). Although residing between the second and third WD-40 repeats characteristic of the CSA protein, A160 is completely conserved in all species that possess a CKN1 homologue. We also describe a mutation in a previously uncharacterised xeroderma pigmentosum group C subject (XP8CA) in the XPC gene (MIM 278720). XP8CA was homozygous for a 2 bp TG deletion in codon 547 resulting in premature termination at codon 572. Immunoblotting of XP8CA extracts confirmed the absence of full-length XPC protein that was present in unaffected cell lines.     

A new UV-sensitive syndrome not belonging to any complementation groups of xeroderma pigmentosum or Cockayne syndrome: siblings showing biochemical characteristics of Cockayne syndrome without typical clinical manifestations

We report here on two siblings who show no clinical manifestations except for slight cutaneous photosensitivity and cutaneous pigmentation but have biochemical characteristics o Cockayne syndrome (CS). Fibroblasts derived DNA synthesis (UDS)_in these cells was at a normal level, recovery of RNA synthesis (RRS) after UV irradiation was severely depressed. Microinjection of bacteriophage T4 endonuclease V into the cells corrected RRS after UV irradiation to a level near normal. These results indicate that DNA repair of cyclobutane-type pyrimidine dimers is impaired in the cells and the biochemical characteristics are similar to these of CS cells. However, cell fusion complementation tests with CS group A and B cells resulted in correction of RRS after UV irradiation. Cell fusion with XP group A, B, D, F and G cells also corrected RRS after UV irradiation, and microinjection of cell extracts prepared from Kps3 cells corrected UDS in XP group C and E cells, indicating that the patients do not belong to any complementation group of XP or CS. These results suggest that the patients have a new UV-sensitive syndrome with a biochemical phenotype of CS.     

Identical male twins and brother with Cockayne syndrome

The clinical, radiological, and neuropathological findings in early onset Cockayne syndrome are illustrated in identical twins and their brother. Their appearance of dwarfism with small head and prominent beaked nose strongly resembled that seen in the Seckel syndrome, but unlike patients with that syndrome they had a normal birth weight (for twins), thick cranial vaults, intracranial calcification, and a severe degree of mental retardation. The twins were deaf and blind, with optic atrophy and retinal pigmentation, while their brother had cataracts. Their hands and feet were large in proportion to their small trunk. They had cutaneous sensitivity to any slight exposure to ultraviolet light and severe neurologic problems with incoordination and spasticity. Radiologic findings included microcephaly, a thick cranial vault, a small pelvis, coxa valga, and “ivory epiphyses” in terminal phalanges of hands and feet. Pathologic findings included atrophy of white matter with widespread patchy demyelination, and massive siderocalcific deposits in the brain, particularly in the basal ganglia and cerebellum. While autosomal recessive inheritance is most likely, formally X-linked inheritance cannot be excluded.     

Radiation-induced chromatid aberrations in Cockayne syndrome and xeroderma pigmentosum group C fibroblasts in relation to cancer predisposition.

We showed previously that the persistence of chromatid breaks and gaps after G2 phase irradiation with X-rays or near-UV visible light characterizes skin fibroblasts from individuals with cancer-prone genetic diseases. This abnormal response appears to result from deficient DNA repair during G2 and to be associated with cancer proneness. We have, therefore, compared the responses of cells from two genetic disorders, Cockayne syndrome (CS) and xeroderma pigmentosum complementation group C(XP-C), both of which exhibit cellular hypersensitivity to sunlight, but only one of which, XP, manifests a high rate of sunlight-induced cancer. CS cells, in contrast to XP cells, showed a normal G2 response to irradiation with either X-rays or near-UV visible light. However, CS cells showed a deficiency in repair of DNA damage inflicted by light during S and G1 phases of the cell cycle. The present results support the concept that deficient DNA repair during G2 phase plays a role in carcinogenesis. This deficient repair in the presence of DNA damage and continuous cell cycling from activation of proto-oncogenes or loss of suppressor genes may be necessary and sufficient for cancer development.     

Pellagra‐like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit

An extremely rare pellagra‐like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra‐like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet‐induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.     

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Cancer, aging, and neurodegeneration are all associated with DNA damage and repair in complex fashions. Aging appears to be a cell and tissue-wide process linked to the insulin-dependent pathway in several DNA repair deficient disorders, especially in mice. Cancer and neurodegeneration appear to have complementary relationships to DNA damage and repair. Cancer arises from surviving cells, or even stem cells, that have down-regulated many pathways, including apoptosis, that regulate genomic stability in a multi-step process. Neurodegeneration however occurs in nondividing neurons in which the persistence of apoptosis in response to reactive oxygen species is, itself, pathological. Questions that remain open concern: sources and chemical nature of naturally occurring DNA damaging agents, especially whether mitochondria are the true source; the target tissues for DNA damage and repair; do the human DNA repair deficient diseases delineate specific pathways of DNA damage relevant to clinical outcomes; if naturally occurring reactive oxygen species are pathological in human repair deficient disease, would anti-oxidants or anti-apoptotic agents be feasible therapeutic agent?     

A summary of mutations in the UV‐sensitive disorders: Xeroderma pigmentosum,Cockayne syndrome,and trichothiodystrophy

The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UV^s) groups. We also recommend that the XP‐group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP‐E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage‐specific DNA binding protein. Hum Mutat 14:9–22, 1999. © 1999 Wiley‐Liss, Inc.