AI Article Synopsis
- Cornelia de Lange syndrome (CdLS) is a developmental disorder marked by distinct facial features, limb malformations, and impairments in growth and cognitive abilities.
- About 65% of CdLS patients have mutations in specific genes (NIPBL, SMC1A, SMC3) that play roles in chromosome stability and gene regulation.
- Research shows that mutated forms of SMC1A and SMC3 bind DNA more tightly than the normal versions, leading to genomic instability and increased sensitivity to DNA-damaging agents, suggesting that these mutations disrupt the normal function between SMC proteins and DNA.
Article Abstract
Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous developmental disorder characterized by facial dysmorphia, upper limb malformations, growth and cognitive retardation. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A and SMC3 are present in approximately 65% of CdLS patients. In addition to their canonical roles in chromosome segregation, the cohesin proteins are involved in other biological processes such as regulation of gene expression, DNA repair and maintenance of genome stability. To gain insights into the molecular basis of CdLS, we analyzed the affinity of mutated SMC1A and SMC3 hinge domains for DNA. Mutated hinge dimers bind DNA with higher affinity than wild-type proteins. SMC1A- and SMC3-mutated CdLS cell lines display genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. We propose that SMC1A and SMC3 CdLS mutations affect the dynamic association between SMC proteins and DNA, providing new clues to the underlying molecular cause of CdLS.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722190 | PMC |
| http://dx.doi.org/10.1093/hmg/ddn369 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Cornelia de Lange Syndrome Accompanied by Cholelithiasis and Nephrolithiasis: A Case Report.
Children (Basel)
November 2024
Departments of Pediatrics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan 49267, Republic of Korea.
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by a distinctive facial appearance, growth/cognitive retardation, developmental delay, skeletal malformation, hypertrichosis, and other abnormalities. Patients with mild CdLS have less severe phenotypes, while retaining representative facial features. Mutations in the genes , , , , and have been associated with CdLS, with mutations in accounting for approximately 60% of cases.
View Article and Find Full Text PDFGenome Instability and Senescence Are Markers of Cornelia de Lange Syndrome Cells.
Cells
December 2024
Institute for Biomedical Technologies, National Research Council, 56124 Pisa, Italy.
Cornelia de Lange syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder. Pathogenic variants in genes encoding the structural subunits and regulatory proteins of the cohesin complex (, , , , and ) are the primary contributors to the pathogenesis of CdLS. Pathogenic variations in these genes disrupt normal cohesin function, leading to the syndrome's diverse and complex clinical presentation.
View Article and Find Full Text PDFA Novel De Novo Variant in Monozygotic Twins with Neurodevelopmental Disorder: New Insights in Clinical Heterogeneity.
Genes (Basel)
September 2024
Medical and Laboratory Genetics Unit, A.O.R.N. "Antonio Cardarelli", 80131 Naples, Italy.
Article Synopsis
- The cohesin complex gene is linked to critical functions like chromosome segregation and DNA repair, and variants can cause disorders with distinct physical and neurological symptoms.
- Two twins with a novel de novo variant in this gene exhibited differing severity of neurodevelopmental delays, with one twin significantly more affected by behavioral and speech difficulties.
- The study suggests variability in clinical presentations related to the gene, possibly influenced by other genetic factors, such as a discovered microduplication on chromosome 15.
Cohesin mutations in acute myeloid leukemia.
Leukemia
November 2024
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
The cohesin complex, encoded by SMC3, SMC1A, RAD21, and STAG2, is a critical regulator of DNA-looping and gene expression. Over a decade has passed since recurrent mutations affecting cohesin subunits were first identified in myeloid malignancies such as Acute Myeloid Leukemia (AML). Since that time there has been tremendous progress in our understanding of chromatin structure and cohesin biology, but critical questions remain because of the multiple critical functions the cohesin complex is responsible for.
View Article and Find Full Text PDFThe cohesin ATPase cycle is mediated by specific conformational dynamics and interface plasticity of SMC1A and SMC3 ATPase domains.
Cell Rep
September 2024
Université de Strasbourg, IGBMC UMR 7104 - UMR-S 1258, 67400 Illkirch, France; CNRS, UMR 7104, 67400 Illkirch, France; INSERM, UMR-S 1258, 67400 Illkirch, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Integrated Structural Biology, 67400 Illkirch, France. Electronic address:
Article Synopsis
- Cohesin is essential for organizing the eukaryotic genome and operates using ATP throughout the cell cycle, although its ATPase activity mechanisms are not well understood.
- This study explores the human cohesin ATPase cycle, revealing specific structural changes in the SMC1A and SMC3 ATPase domains during the process.
- The SMC3 domain exhibits flexibility that is influenced by ATP binding, while its interaction with NIPBL and DNA stabilizes the structure, ultimately impacting the formation of the DNA-binding chamber.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!