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A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome

Nature Genetics volume 33, pages 497–501 (2003)Cite this article

Abstract

Seckel syndrome (OMIM 210600) is an autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly and mental retardation. Clinically, Seckel syndrome shares features in common with disorders involving impaired DNA-damage responses, such as Nijmegen breakage syndrome (OMIM 251260) and LIG4 syndrome (OMIM 606593). We previously mapped a locus associated with Seckel syndrome to chromosome 3q22.1–q24 in two consanguineous Pakistani families1. Further marker analysis in the families, including a recently born unaffected child with a recombination in the critical region, narrowed the region to an interval of 5 Mbp between markers D3S1316 and D3S1557 (145.29 Mbp and 150.37 Mbp). The gene encoding ataxia–telangiectasia and Rad3–related protein (ATR) maps to this region2,3. A fibroblast cell line derived from an affected individual displays a defective DNA damage response caused by impaired ATR function. We identified a synonymous mutation in affected individuals that alters ATR splicing. The mutation confers a phenotype including marked microcephaly (head circumference 12 s.d. below the mean) and dwarfism (5 s.d. below the mean). Our analysis shows that UV-induced ATR activation can occur in non-replicating cells following processing by nucleotide excision repair.

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Figure 1: F02-98 cells show an impaired response to DNA damage.
Figure 2: F02-98 cells are hypersensitive to ultraviolet radiation and mitomycin C.
Figure 3: F02-98 cells show residual ATR expression and protein phosphorylation, and defective phosphorylation can be complemented by ATR cDNA.
Figure 4: Identification of a mutation in ATR in individuals with Seckel syndrome.
Figure 5: In vivo splicing assay shows that the 2101A→G transition affects splicing.
Figure 6: ATR activation by ultraviolet radiation in non-replicating cells requires processing by nucleotide-excision repair.

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Acknowledgements

We thank A. Krainer and W. Fairbrother for discussions and A. Carr for the gift of ATR cDNA. This work was supported by the Medical Research Council, the Human Frontiers Science Programme, the Department of Health, the Primary Immunodeficiency Association, the Leukaemia Research Fund, the Wellcome Trust and Newcastle Healthcare Charity. M.O'D. is supported by the Leukaemia Research Fund.

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Author notes

  1. Mark O'Driscoll and Victor L. Ruiz-Perez: These authors contributed equally to this work.

Authors and Affiliations

  1. Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, UK

    Mark O'Driscoll & Penny A. Jeggo

  2. Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne, UK

    Victor L. Ruiz-Perez & Judith A. Goodship

  3. Molecular Medicine Unit, St. James' University Hospital, Leeds, UK

    C. Geoffrey Woods

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  1. Mark O'Driscoll
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  2. Victor L. Ruiz-Perez
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Correspondence to Penny A. Jeggo.

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O'Driscoll, M., Ruiz-Perez, V., Woods, C. et al. A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome. Nat Genet 33, 497–501 (2003). https://doi.org/10.1038/ng1129

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