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

By M. O’Driscoll, V. Ruiz-Perez, C. Woods, P. Jeggo, J. Goodship. Nature Genetics, 2003

855 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/4c952ce9cb4584ceab6f85766706218940d24181

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Stephen P. Jackson
2. J. Bartek
3. J. Lukas
4. P. Jeggo
5. C. Lukas
6. M. O’Driscoll
7. J. Falck
8. D. Meek

In Oncology

1. Stephen P. Jackson
2. J. Bartek
3. J. Lukas
4. P. Jeggo
5. C. Lukas
6. M. O’Driscoll
7. J. Falck
8. D. Meek

In Pathology and Forensic Medicine

1. J. Bartek
2. Stephen P. Jackson

Citations in the corpus

• ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks (2006, methodology): “and human cell lines lacking ATR do not exist, we used ATR-Seckel cells that express very low levels of AT”
• Tumour suppression by p53: a role for the DNA damage response? (2009, background): “cgi?id=210600">Seckel syndrome have substantially impaired but not abolished ATR function; however, they do not seem to show an increased susceptibility to cance”
• The role of double-strand break repair — insights from human genetics (2006, background): “fcgi?cmd=Retrieve&db=OMIM&dopt=DocSum&list_uids=210600,606744,608664">Seckel syndrome (ATR-Seckel) — a disorder that is characterized by proportionate dwarfism, developmental delay and severe microcephal”
• p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. (2007, methodology): “ATM and ATR Are Required for p38MAPK/MK2 Activation following Genotoxin-Induced DNA Damage but Not in Response to UV Irradiation We analyzed the p38MAPK/MK2 activation profile in ATM-deficient and ATR-defective fibroblasts (O’Driscoll et al., 2003) (Figures S1A–S1D and S2 in the Supplemental Data av”
• Mechanisms and pathways of growth failure in primordial dwarfism. (2011, background): “The first gene to be identified was ATR, a key phosphotidyl-inosine-3 kinase (PI3K)-like kinase that signals DNA damage (O’Driscoll et al. 2003).”