title: 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.
authors.affiliation: Nagasaki University Research Centre for Genomic Instability and Carcinogenesis, Nagasaki University, Sakamoto, Nagasaki, Japan. m.o-driscoll@sussex.ac.uk
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
authors.forename: Sarah
authors.initials: S
authors.lastname: Walker
authors.forename: Tom
authors.initials: T
authors.lastname: Stiff
authors.forename: Emma
authors.initials: E
authors.lastname: Hobson
authors.forename: Siripan
authors.initials: S
authors.lastname: Limsirichaikul
authors.forename: Gillian
authors.initials: G
authors.lastname: Carpenter
authors.forename: Katrina
authors.initials: K
authors.lastname: Prescott
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Byrd
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsuse
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Pradeep
authors.initials: P
authors.lastname: Vasudevan
authors.forename: Margaret
authors.initials: M
authors.lastname: Barrow
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018389:Codon, Nonsense; D065817:Congenital Microtia; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D004423:Ear / Q000002:abnormalities / Q000473:pathology; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D008844:Micrognathism / Q000235:genetics / Q000473:pathology; D010009:Osteochondrodysplasias / Q000235:genetics / Q000473:pathology; D010329:Patella / Q000002:abnormalities / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D015398:Signal Transduction / Q000235:genetics
chemical_list: C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases