Analysis of novel missense ATR mutations reveals new splicing defects underlying Seckel syndrome

Abstract

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.

Versatility of the Mec1ATM/ATR signaling network in mediating resistance to replication, genotoxic, and proteotoxic stresses

“…At the cellular level, loss of ATM/ATR function results in genome instability and acute sensitivity to genotoxic agents. In humans, inactivation of ATM or ATR leads to ataxia-telangiectasia (A-T) or Seckel syndrome, respectively, a rare autosomal recessive disease characterized by a constellation of symptoms including cerebellum ataxia, cancer, diabetes, growth retardation and/or microcephaly (O’Driscoll et al 2003; Llorens-Agost et al 2018). While deficits in the DDR underpin some of these conditions, they do not adequately account for all clinical manifestations of A-T and Seckel syndrome.…”

A novel leaky splice variant in centromere protein J (CENPJ)‐associated Seckel syndrome

“…Based on available literature, the causal role of such intronic variants leading to exon‐skipping have been reported previously in PLK4 in Seckel syndrome (Dinçer et al., 2017). Furthermore, exonic regulatory variants in ATR (SCKL1) (Llorens‐Agost et al., 2018) and TRAIP (SCKL9) (Harley et al., 2016) also result in disease manifestation. Therefore, we may infer that regulatory variant(s) in some genes involved in cell cycle ( CENPJ ) and DNA damage repair ( ATR ) are more likely to be causal for microcephalies and Seckel syndrome.…”

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

“…Mutations in ATR are much rarer that in ATM. They are not associated with hereditary breast and ovarian cancer (HBOC) syndrome, only with Seckel syndrome, an autosomal recessive disorder not implicated in malignancy [271].…”