title: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.
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 families. 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 region. 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.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Victor L
authors.initials: VL
authors.lastname: Ruiz-Perez
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002460:Cell Line; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012326:RNA Splicing; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: D018797:Cell Cycle Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases