Analysis of novel missense ATR mutations reveals new splicing defects underlying Seckel syndrome.
Marta Llorens-AgostJanna LuessingAmandine van BenedenJohn EykelenboomDawn O'ReillyLouise S BicknellJohn J ReynoldsMarianne van KoegelenbergMatthew E HurlesAngela F BradyAndrew P JacksonGrant S StewartNoel F LowndesPublished in: Human mutation (2018)
Ataxia Telangiectasia and Rad3 related (ATR) is one of the main regulators of the DNA damage response. It coordinates cell cycle checkpoint activation, replication fork stability, restart and origin firing to maintain genome integrity. Mutations of the ATR gene have been reported in Seckel patients, who suffer from a rare genetic disease characterized by severe microcephaly and growth retardation. Here, we report the case of a Seckel patient with compound heterozygous mutations in ATR. One allele has an intronic mutation affecting splicing of neighboring exons, the other an exonic missense mutation, producing the variant p.Lys1665Asn, of unknown pathogenicity. We have modeled this novel missense mutation, as well as a previously described missense mutation p.Met1159Ile, and assessed their effect on ATR function. Interestingly, our data indicate that both missense mutations have no direct effect on protein function, but rather result in defective ATR splicing. These results emphasize the importance of splicing mutations in Seckel Syndrome.
Keyphrases
- dna damage response
- intellectual disability
- cell cycle
- dna repair
- dna damage
- early onset
- autism spectrum disorder
- cell proliferation
- case report
- genome wide
- zika virus
- copy number
- machine learning
- transcription factor
- electronic health record
- tyrosine kinase
- oxidative stress
- big data
- escherichia coli
- artificial intelligence
- candida albicans