title: Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations.
abstract: Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity.
authors.affiliation: Genome Dynamics in the Immune System, INSERM, Paris, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Mokrani-Benhelli
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gaillard
authors.forename: Patricia
authors.initials: P
authors.lastname: Biasutto
authors.forename: Tangui
authors.initials: T
authors.lastname: Le Guen
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.forename: Nadia
authors.initials: N
authors.lastname: Vasquez
authors.forename: Jun
authors.initials: J
authors.lastname: Komatsu
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Conseiller
authors.forename: Capucine
authors.initials: C
authors.lastname: Pïcard
authors.forename: Eliane
authors.initials: E
authors.lastname: Gluckman
authors.forename: Christine
authors.initials: C
authors.lastname: Francannet
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D002648:Child; D055028:Comparative Genomic Hybridization; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012326:RNA Splicing; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases