Cellular models to identify the mechanisms underlying the chromosome abnormalities of cohesinopathy patients

Cohesinopathies are genetic diseases, associated with growth and mental retardation, various malformations of the hands, legs and bones, and distinct facial features. The three well- known cohesinopathies are Cornelia de Lange Syndrome (CdLS), Roberts syndrome (RBS)/SC Phocomelia, and Warsaw Breakage syndrome (WABS). CdLS is estimated to occur with a prevalence of at least 1 in 10,000 individuals, whereas RBS and WABS are very rare diseases. Patients suffering from RBS and WABS exhibit symptoms that overlap with those of another chromosome instability syndrome, Fanconi anemia, and thus they may be misdiagnosed. Usually the individuals affected with cohesinopathies die very young, but the life span is highly correlated with the severity of the growth and developmental defects. A recent study of 62 Italian patients with a clinical diagnosis of CdLS showed wide variability in the symptoms. The genes responsible for cohesinopathies are involved in maintaining the proximity/cohesion between the sister chromatids, acting similarly with a glue. When these cohesion factors are defective, the chromatids are separated and the chromosomes accumulate lesions and aberrant structures. Our research project aims at clarifying the role of these cohesion factors in protecting the chromosomes and in maintaining the right distance between the sister chromatids so that DNA processes such as replication and transcription that are essential for cellular life can occur normally. Our research aims at unmasking the factors that contribute in generating chromosomal abnormalities in cohesinopathy patients and at identifying potential pharmacological targets.