Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Abstract

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

“…However, they also reported one family (P21) from Saudi Arabia that resembles the phenotype of MMS in the First Nations population and which, remarkably, contains the same homozygous mutation, suggesting that a range of hypomorphic DONSON mutations cause a wide spectrum of MPD and microcephalic syndromes. Reynolds et al (2017) further present extensive cell biological evidence for an essential role for DONSON in the replication fork mediating genome replication. Altogether, the unique MMS cases we have studied and the above related syndromes define DONSON as a novel human disease gene and will help inform future investigations of its essential function in cellular replication and organismal development.…”

“…Indeed, during review of this manuscript, Reynolds et al (2017) published a series of cases of recessive, hypomorphic mutations in DONSON causing primary microcephaly, microcephaly with short stature, and MPD. Most of the phenotypes they report are nonlethal and milder than MMS, implying that the mutations had milder effects on DONSON function than the MMS mutation.…”

Further Delineation of the Microcephaly-Micromelia Syndrome Associated with Loss-of-Function Variants in DONSON

“…In this syndrome, patients have short stature, microcephaly, variable hand or feet deformities, and intellectual or speech delay may occur. Overall, 21 disease-causing variants have been reported in this gene so far, inherited as homozygous or compound heterozygous variants/haplotypes [Evrony et al, 2017;Reynolds et al, 2017;Schulz et al, 2018]. In this report, we present another family with 2 affected siblings born with MIMIS, carrying another homozygous loss-of-function variant in the DONSON gene and review the clinical phenotype of previously reported cases.…”

“…MIMIS (OMIM 251230 [Evrony et al, 2017;Reynolds et al, 2017]. This variant has been shown to cause complete loss of function of this gene due to the altered splicing and the shift generated in the reading frame leading to the transcript degradation by nonsense-mediated decay [Evrony et al, 2017].…”

Genome integrity and disease prevention in the nervous system

“…Replication stress is connected to a variety of syndromes that have neurologic involvement (Table 1; Harley et al 2016;O'Driscoll 2017;Reynolds et al 2017). A key responder to replication stress is the DNA damage response serine/threonine kinase ATR (A-T and rad3-related) (Nam and Cortez 2011;Marechal and Zou 2013).…”