<p>Spotlight on Warsaw Breakage Syndrome</p>

Abstract

Warsaw breakage syndrome (WABS) is a very rare recessive hereditary disease caused by mutations in the gene coding for the DNA helicase DDX11, involved in genome stability maintenance and sister cohesion establishment. Typical clinical features observed in WABS patients include growth retardation, facial dysmorphia, microcephaly, hearing loss due to cochlear malformations and, at cytological level, sister chromatid cohesion defects. Molecular bases of WABS have not yet been elucidated, due to lack of disease animal model systems and limited knowledge of the DDX11 physiological functions. However, WABS is considered to belong to the group of cohesinopathies, genetic disorders due to mutations of subunits or regulators of cohesin, the protein complex responsible for tethering sister chromatids from the time of their synthesis till they separate in mitosis. Recent evidences suggest that cohesin and its regulators have additional key roles in chromatin organization by promoting the formation of chromatin loops. This “non-canonical” function of cohesin is expected to impact gene transcription during cell differentiation and embryonic development and its dis-regulation, caused by mutation/loss of genes encoding cohesin subunits or regulators, could originate the developmental defects observed in cohesinopathies. Ethiopathogenesis of WABS is discussed in line with these recent findings and evidence of a possible role of DDX11 as a cohesin regulator.

The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer

“…All these DNA helicases are genetically linked to rare hereditary diseases that display genome instability features and, in some cases, also cancer susceptibility. Bi-allelic mutations of the DDX11 gene cause Warsaw breakage syndrome (WABS), a rare pathology that is characterized by a complex spectrum of symptoms including pre- and post-natal growth defects, microcephaly, various degree of intellectual disability, heart defects, and at cytological level sister chromatid cohesion abnormalities, giving rise to an altered chromosome morphology [ 10 ]. The chromosomal cohesion anomalies observed in fibroblasts or lymphoblasts derived from WABS patients or other DDX11-deficient cells consist of a premature centromere division (PCD), characterized by a loosened centromere constriction, likely due to repulsion of the corresponding heterochromatic regions; besides, in an appreciable number of metaphase chromosome spreads of the above cell lines, all the sister chromatid pairs appear completely separated, a condition defined as premature chromatid separation (PCS) [ 11 ].…”

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

“…Warsaw Breakage Syndrome (WABS) was discovered in 2010 in a patient displaying remarkable clinical overlap with Fanconi anemia (FA), a DNA damage syndrome characterized by impaired DNA crosslink repair, including growth retardation, microcephaly, and abnormal skin pigmentation, although bone marrow failure was not observed 1 . Both FA and WABS patient-derived cells exhibit mitomycin C (MMC)-induced chromosomal breaks but only WABS cells typically show spontaneous loss of sister chromatid cohesion at metaphase 2 , 3 . Such cohesion loss is significantly exacerbated by treatment with MMC or the topoisomerase I inhibitor camptothecin (CPT).…”

Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations

“…The ASD patient of FAM2 does not have any severe microcephaly or facial dysmorphic features, although other phenotypic findings of the WBS were not evaluated in this proband. WBS is an ultra‐rare disorder, the estimated disease frequency is smaller than 1/1 × 10 6 and only 16 cases have been reported in the medical literature to date 73 . Mut2 is a missense variant (p.(V774L)) and Val residue is completely conserved in all vertebrate lineages (data not shown) and highly conserved in eukaryotes (see Supporting information, Figure D).…”

“…In addition, two healthy sibs of the proband do not have the two copies of the mutant alleles (see Supporting information, Figure A ) and this situation supports our prediction. Bi‐allelic mutations of the DDX11 gene are associated with WBS, which is also classified as a cohesinopathy disorder because these patients' metaphase chromosomes are characterized with a “railway” view as a result of premature separations of the cohesins 73 . It has been shown that the absences of Ddx11 results in embryonic lethality at embryonic day 10.5 in the mouse 103 .…”