%0 Journal Article
%T Identification of the First ATRIP每Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR每ATRIP Seckel Syndrome
%A Tomoo Ogi equal contributor
%A Sarah Walker equal contributor
%A Tom Stiff
%A Emma Hobson
%A Siripan Limsirichaikul
%A Gillian Carpenter
%A Katrina Prescott
%A Mohnish Suri
%A Philip J. Byrd
%A Michiko Matsuse
%A Norisato Mitsutake
%A Yuka Nakazawa
%A Pradeep Vasudevan
%A Margaret Barrow
%A Grant S. Stewart
%A A. Malcolm R. Taylor
%A Mark O'Driscoll
%A Penny A. Jeggo
%J PLOS Genetics
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pgen.1002945
%X 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每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每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每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每deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR每deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR每ATRIP deficient sub-class of Seckel Syndrome. ATR每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每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每ATRIP Seckel Syndrome to be defined.
%U http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002945