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Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome
http://hdl.handle.net/10069/31141
http://hdl.handle.net/10069/3114113d014dd-1edd-4537-8ebb-3afd03b3778f
名前 / ファイル | ライセンス | アクション |
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PLoSGen8_1002945.pdf (1.7 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2013-03-29 | |||||
タイトル | ||||||
タイトル | Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者 |
Ogi, Tomoo
× Ogi, Tomoo× Walker, Sarah× Stiff, Tom× Hobson, Emma× Limsirichaikul, Siripan× Carpenter, Gillian× Prescott, Katrina× Suri, Mohnish× Byrd, Philip J.× Matsuse, Michiko× Mitsutake, Norisato× Nakazawa, Yuka× Vasudevan, Pradeep× Barrow, Margaret× Stewart, Grant S.× Taylor, A. Malcolm R.× O'Driscoll, Mark× Jeggo, Penny A. |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be defined. | |||||
書誌情報 |
PLoS Genetics 巻 8, 号 11, p. e1002945, 発行日 2012-11-08 |
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出版者 | ||||||
出版者 | Public Library of Science | |||||
EISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 15537404 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | 10.1371/journal.pgen.1002945 | |||||
権利 | ||||||
権利情報 | © 2012 Ogi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
引用 | ||||||
内容記述タイプ | Other | |||||
内容記述 | PLoS Genetics, 8(11), e1002945; 2012 |