NA18366
DNA from Fibroblast
Description:
SECKEL SYNDROME
ATAXIA-TELANGIECTASIA AND RAD3-RELATED; ATR
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases |
| Class |
Disorders of Connective Tissue, Muscle, and Bone |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
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Cell Type
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Fibroblast
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Transformant
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Untransformed
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Sample Source
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DNA from Fibroblast
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Race
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East Indian
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Ethnicity
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PAKISTANI
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Family Member
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1
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Relation to Proband
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proband
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Confirmation
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Molecular characterization before cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| PDL at Freeze |
6.58 |
| Passage Frozen |
19 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin confirmed by LINE assay |
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| Gene |
ATR |
| Chromosomal Location |
3q22-q24 |
| Allelic Variant 1 |
601215.0001; SECKEL SYNDROME |
| Identified Mutation |
2101A>G; In 2 Pakistani families, O'Driscoll et al. (Nature Genet. 33: 497-501, 2003) found that a homozygous translationally silent (synonymous) single base change, 2101A-G, segregated with Seckel syndrome (210600). The mutation resulted in the use of 2 cryptic splice-donor sites in exon 9. Loss of exon 9 and use of the cryptic splice-donor sites introduced a stop codon in the next exon. Because of the profound effect on splicing efficiency, there were reduced but residual levels of normal transcript and protein. The severity of this hypomorphic mutation was shown by the marked microcephaly and dwarfism observed in the affected individuals and was consistent with the embryonic and somatic lethality seen in the absence of ATR (Brown and Baltimore, Genes Dev. 14: 397-402, 2000; Cortez et al., Science 294: 1713-1716, 2001). This was the first evidence of a clinical disorder associated with impaired ATR signaling. |
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| Gene |
ATR |
| Chromosomal Location |
3q22-q24 |
| Allelic Variant 2 |
601215.0001; SECKEL SYNDROME |
| Identified Mutation |
2101A>G; In 2 Pakistani families, O'Driscoll et al. (Nature Genet. 33: 497-501, 2003) found that a homozygous translationally silent (synonymous) single base change, 2101A-G, segregated with Seckel syndrome (210600). The mutation resulted in the use of 2 cryptic splice-donor sites in exon 9. Loss of exon 9 and use of the cryptic splice-donor sites introduced a stop codon in the next exon. Because of the profound effect on splicing efficiency, there were reduced but residual levels of normal transcript and protein. The severity of this hypomorphic mutation was shown by the marked microcephaly and dwarfism observed in the affected individuals and was consistent with the embryonic and somatic lethality seen in the absence of ATR (Brown and Baltimore, Genes Dev. 14: 397-402, 2000; Cortez et al., Science 294: 1713-1716, 2001). This was the first evidence of a clinical disorder associated with impaired ATR signaling. |
| Remarks |
Clinically affected; striking microcephaly; 106 cm (-4.8 SD) tall with a head circumference of 37 cm (-12 SD) at age 9; receding forehead; micrognathia; prominent nose; crowded teeth; dental malocclusion; mild thoracic kyphosis; moderate mental retardation; first walked at age 7 years; a mutation at nucleotide 2101A>G causes increased levels of skipping exon 9 and activation of two cryptic splicing events from sites in exon 9 leading to termination in exon 10; splicing of exon 9 is inefficient in mutant cells, but a small amount of correctly spliced mRNA was observed; fibroblast cell line derived from the proband showed an impaired response to DNA damage induced by UV radiation but had a normal in response to ionizing radiation; cells showed a low level of expression of the ATR protein; cells are hypersensitive to mitomycin C and UV in a survival assay (see more information in PMID: 12640452); subject referred to as V6 in publication by Goodship, et al (PMID: 10889046) and as F02-98 in several other publications. |
| Kidiyoor GR, Li Q, Bastianello G, Bruhn C, Giovannetti I, Mohamood A, Beznoussenko GV, Mironov A, Raab M, Piel M, Restuccia U, Matafora V, Bachi A, Barozzi S, Parazzoli D, Frittoli E, Palamidessi A, Panciera T, Piccolo S, Scita G, Maiuri P, Havas KM, Zhou ZW, Kumar A, Bartek J, Wang ZQ, Foiani M, ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration Nature communications11:4828 2019 |
| PubMed ID: 32973141 |
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| Ichisima J, Suzuki NM, Samata B, Awaya T, Takahashi J, Hagiwara M, Nakahata T, Saito MK, Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model Journal of human genetics64:445-458 2018 |
| PubMed ID: 30846821 |
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| Ray A, Milum K, Battu A, Wani G, Wani AA, NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites DNA repair64:445-458 2012 |
| PubMed ID: 23422745 |
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| So EY, Ausman M, Saeki T, Ouchi T, Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis Cell death & disease2:e128 2011 |
| PubMed ID: 21390062 |
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| Pennarun G, Hoffschir F, Revaud D, Granotier C, Gauthier LR, Mailliet P, Biard DS, Boussin FD, ATR contributes to telomere maintenance in human cells Nucleic acids research38:2955-63 2010 |
| PubMed ID: 20147462 |
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| Wilson PF, Nham PB, Urbin SS, Hinz JM, Jones IM, Thompson LH, Inter-individual variation in DNA double-strand break repair in human fibroblasts before and after exposure to low doses of ionizing radiation Mutation research683:91-7 2009 |
| PubMed ID: 19896956 |
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| Carson CT, Orazio NI, Lee DV, Suh J, Bekker-Jensen S, Araujo FD, Lakdawala SS, Lilley CE, Bartek J, Lukas J, Weitzman MD, Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection The EMBO journal28:652-62 2008 |
| PubMed ID: 19197236 |
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| Yan J, Yang XP, Kim YS, Jetten AM, RAP80 responds to DNA damage induced by both ionizing radiation and UV irradiation and is phosphorylated at Ser 205 Cancer research68:4269-76 2008 |
| PubMed ID: 18519686 |
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| Matsumoto M, Yaginuma K, Igarashi A, Imura M, Hasegawa M, Iwabuchi K, Date T, Mori T, Ishizaki K, Yamashita K, Inobe M, Matsunaga T, Perturbed gap-filling synthesis in nucleotide excision repair causes histone H2AX phosphorylation in human quiescent cells Journal of cell science120:1104-12 2007 |
| PubMed ID: 17327276 |
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| Stokes MP, Rush J, Macneill J, Ren JM, Sprott K, Nardone J, Yang V, Beausoleil SA, Gygi SP, Livingstone M, Zhang H, Polakiewicz RD, Comb MJ, Profiling of UV-induced ATM/ATR signaling pathways Proceedings of the National Academy of Sciences of the United States of America104:19855-60 2007 |
| PubMed ID: 18077418 |
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| Bergink S, Salomons FA, Hoogstraten D, Groothuis TA, de Waard H, Wu J, Yuan L, Citterio E, Houtsmuller AB, Neefjes J, Hoeijmakers JH, Vermeulen W, Dantuma NP, DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A Genes & development20:1343-52 2006 |
| PubMed ID: 16702407 |
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| Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG, Bazett-Jones DP, Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR The Journal of cell biology175:55-66 2006 |
| PubMed ID: 17030982 |
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| Wu X, Shell SM, Yang Z, Zou Y, Phosphorylation of nucleotide excision repair factor xeroderma pigmentosum group A by ataxia telangiectasia mutated and Rad3-related-dependent checkpoint pathway promotes cell survival in response to UV irradiation Cancer research66:2997-3005 2006 |
| PubMed ID: 16540648 |
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| Andreassen PR, D'Andrea AD, Taniguchi T, ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev18(16):1958-63 2004 |
| PubMed ID: 15314022 |
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| O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA, A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet33(4):497-501 2003 |
| PubMed ID: 12640452 |
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| Goodship J, Gill H, Carter J, Jackson A, Splitt M, Wright M, Autozygosity mapping of a seckel syndrome locus to chromosome 3q22. 1-q24. Am J Hum Genet67(2):498-503 2000 |
| PubMed ID: 10889046 |
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| Goodship J, Gill H, Carter J, Jackson A, Splitt M, Wright M, Autozygosity mapping of a seckel syndrome locus to chromosome 3q22. 1-q24. Am J Hum Genet67(2):498-503 2000 |
| PubMed ID: 30010936 |
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