10.1371/journal.pgen.1002945 Tomoo Ogi Tomoo Ogi Sarah Walker Sarah Walker Tom Stiff Tom Stiff Emma Hobson Emma Hobson Siripan Limsirichaikul Siripan Limsirichaikul Gillian Carpenter Gillian Carpenter Katrina Prescott Katrina Prescott Mohnish Suri Mohnish Suri Philip J. Byrd Philip J. Byrd Michiko Matsuse Michiko Matsuse Norisato Mitsutake Norisato Mitsutake Yuka Nakazawa Yuka Nakazawa Pradeep Vasudevan Pradeep Vasudevan Margaret Barrow Margaret Barrow Grant S. Stewart Grant S. Stewart A. Malcolm R. Taylor A. Malcolm R. Taylor Mark O'Driscoll Mark O'Driscoll Penny A. Jeggo Penny A. Jeggo Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome Public Library of Science 2012 mutations atr seckel syndrome 2012-11-08 02:03:16 Dataset https://plos.figshare.com/articles/dataset/Identification_of_the_First_ATRIP_Deficient_Patient_and_Novel_Mutations_in_ATR_Define_a_Clinical_Spectrum_for_ATR_ATRIP_Seckel_Syndrome__/117396 <div><p>A homozygous mutational change in the <em>Ataxia-Telangiectasia and RAD3 related</em> (<em>ATR</em>) 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 <em>ATRIP</em>, 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 <em>ATRIP</em> resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one <em>ATRIP</em> 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 <em>ATR</em>, 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.</p> </div>