Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome

Abstract

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. Seckel Syndrome (SS) is a rare human disorder characterised by small head circumference and delayed growth. Patients can show additional features including abnormal bone development, receding chins, sloping foreheads, and small ears. In 2003, we identified ataxia telangiectasia and Rad3 related (ATR) as a causal genetic defect in two related families displaying SS. However, additional patients with mutations in ATR have not hitherto been identified. Here, we describe two further patients with novel mutations in ATR. Additionally, we identify a patient with mutations in ATRIP, which encodes an interacting partner of ATR, representing a novel genetic defect causing SS. ATR functions to promote the ability of cells to recover from difficulties encountered during replication. We show that patient-derived cells have reduced ATR and ATRIP protein levels and defective ATR/ATRIP function. Our identification of further ATR–ATRIP defective patients and a consideration of their clinical features aids the characterisation and identification of this form of SS and provides insight into the role played by the ATR–ATRIP complex during development.