Authors Houda Mokrani-Benhelli and Laetitia Gaillard equally contributed to this work.
Primary Microcephaly, Impaired DNA Replication, and Genomic Instability Caused by Compound Heterozygous ATR Mutations
Article first published online: 20 DEC 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 2, pages 374–384, February 2013
How to Cite
Mokrani-Benhelli, H., Gaillard, L., Biasutto, P., Le Guen, T., Touzot, F., Vasquez, N., Komatsu, J., Conseiller, E., Pïcard, C., Gluckman, E., Francannet, C., Fischer, A., Durandy, A., Soulier, J., de Villartay, J.-P., Cavazzana-Calvo, M. and Revy, P. (2013), Primary Microcephaly, Impaired DNA Replication, and Genomic Instability Caused by Compound Heterozygous ATR Mutations. Hum. Mutat., 34: 374–384. doi: 10.1002/humu.22245
Communicated by Stylianos E. Antonarakis
Contract grant sponsors: Institut National de la Santé et de la Recherche Médicale; Institut National du Cancer (INCa)/Cancéropôle Ile de France; Ligue National contre le Cancer (Equipe labellisée La Ligue); Fondation Imagine.
- Issue published online: 29 JAN 2013
- Article first published online: 20 DEC 2012
- Accepted manuscript online: 30 OCT 2012 07:05AM EST
- Manuscript Accepted: 22 OCT 2012
- Manuscript Received: 14 MAY 2012
- Institut National de la Santé et de la Recherche Médicale
- Institut National du Cancer (INCa)/Cancéropôle Ile de France
- Ligue National contre le Cancer (Equipe labellisée La Ligue)
- Fondation Imagine
- primary microcephaly;
- Seckel syndrome;
- DNA replication;
- genomic instability
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.