Repository NIGMS Human Genetic Cell Repository
Subcollection Heritable Diseases
Class Disorders of Connective Tissue, Muscle, and Bone
Cell Type Fibroblast
Transformant Untransformed
Race East Indian
Ethnicity PAKISTANI
Family Member 1
Relation to Proband proband
Confirmation Molecular characterization before cell line submission to CCR
Species Homo sapiens
Common Name Human
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.
PDL at Freeze 6.58
Passage Frozen 19
 
IDENTIFICATION OF SPECIES OF ORIGIN Species of Origin confirmed by LINE assay
 
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.
 
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.
Remark 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.
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
No data is available
Passage Frozen 19
Split Ratio 1:2
Temperature 37 C
Percent CO2 5%
Percent O2 3%
Medium Eagles Minimum Essential Medium with Earle's salts:Dulbecco's modified MEM
Serum 15% fetal bovine serum Not inactivated
Substrate Commercially-treated plastic