Cornelia De Lange Syndrome

What is Cornelia De Lange Syndrome?

Cornelia de Lange syndrome (CdLS), also known as Amsterdam dwarfism, is a multiple congenital dysplasia syndrome described in 1933. CdLS is a rare genetic disorder that mainly resulted from mutations in important developmental genes, such as NIPBL, SMC1A, SMC3 genes. CdLS affects both males and females with estimated morbidity of about 1/1,0000-1/30,000. CdLS has a broad range of characterized symptoms ranging from mild to severe, such as:

• Special face with long and thick eyebrows, short nose, and nostril anteversion.
• Developmental retardation in utero and/or after birth.
• Abnormal structure or function of organs, such as congenital diaphragmatic hernia, pyloric stenosis, Ventricular septal defect, gastrointestinal or musculoskeletal abnormalities, etc.
• Cognitive and intellectual disabilities.

Causes of Cornelia De Lange Syndrome

As a hereditary order, CdLS is considered to be caused by spontaneous genetic mutations, especially seven genes associated with growth and development: NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8, and ANKRD11. And there are still many more genes related to chromatin regulation that have yet to be identified, which are mainly implicated to affect cohesin, an important regulator for chromosome bioactivities and cell cycle stages.

Critical Proteins or Genes in Cornelia De Lange Syndrome Pathogenesis

The specific pathological mechanism of CdLS is still under exploration. But abnormalities in the function of the cohesin complex, which acts as a critical gene expression regulator, have been indicated to be closely related to CdLS pathogenesis. Identification of proteins or genes that are related to cohesin expression and function is beneficial to further diagnosis and treatment development of CdLS. Here list some of these important proteins:

1. Nipped-B-like protein (NIPBL). NIPBL is a hook-shaped protein playing important role in loading the cohesin complex onto DNA or to the sites of DNA damage. Also, it involves improving cortical neuron migration in brain development through regulating the transcription of key genes.
2. Structural maintenance of chromosomes protein 1A (SMC1A). The significance of SMC1A for CdLS pathogenesis is that it is an essential component of the cohesin complex involving chromosome cohesion during the cell cycle and in DNA repair. And SMC1A also plays roles in spindle pole assembly, DNA repair, and DNA entrapping.
3. Structural maintenance of chromosomes protein 3 (SMC3). Similar to SMC1A, SMC3 also is a central subunit of the cohesin complex. It is also an important member of the SMC protein family which plays important actions in chromosome segregation, chromosome condensation, and DNA repair.
4. Double-strand-break repair protein rad21 homolog (RAD21). RAD21 also is a critical component of the cohesin complex, which together with SMC1A and SMC3 form the tripartite ring-like structure of the cohesin complex. Additionally, it also regulates sister chromatid cohesion, spindle pole assembly, apoptosis, and other diverse chromatin-related functions and cellular processes.
5. Other important proteins related to CdLS pathogenesis include bromodomain containing 4 (BRD4), histone deacetylase 8 (HDAC8), ankyrin repeat domain 11 (ANKRD11), and so forth.

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