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Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations

Houda Mokrani-Benhelli1, Laetitia Gaillard, Patricia Biasutto

  • 1Genome Dynamics in the Immune System, INSERM, Paris, France.

Human Mutation
|November 1, 2012
PubMed

Insights

Ataxia telangiectasia and Rad3-related (ATR) kinase deficiency causes primary microcephaly and genomic instability. This study identifies new ATR mutations, highlighting its critical role in DNA replication and genome integrity.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are crucial kinases regulating DNA-damage responses (DDR).
  • ATR signaling defects are linked to Seckel syndrome, a rare genetic disorder featuring microcephaly and growth retardation.
  • Previously, only one hypomorphic ATR splicing mutation was reported in Seckel syndrome patients.

Observation:

  • This study reports the first case of primary microcephaly with compound heterozygous ATR mutations.
  • The identified mutations include a large genomic deletion and a missense mutation affecting ATR splicing, leading to significantly reduced ATR expression.
  • Patient cells exhibited altered DNA replication parameters and genomic instability, confirmed by DNA combing and FISH analyses.

Findings:

  • ATR plays a critical role in controlling DNA replication fidelity.
  • ATR deficiency profoundly impacts DNA replication parameters and leads to genomic instability.
  • The findings reveal novel compound heterozygous mutations in ATR associated with primary microcephaly.

Implications:

  • This research underscores the essential function of ATR in maintaining genome integrity during DNA replication.
  • It highlights the nonredundant roles of ATM and ATR in cellular responses to DNA damage.
  • The study provides new insights into the genetic basis of Seckel syndrome and related disorders.

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