Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is an autosomal dominant disorder arising due to haploinsufficiency in heterozygote individuals. Individuals with CdLS are attributed by delayed growth and development, neurological impairments, malfunctioning of organ systems and musculoskeletal deformations. The molecular mechanism underlying this disorder is situated in mutations of the genes which supposedly produce essential proteins that aid the process of cohesion during cell division. These genes include those that directly form the cohesin complex: SMC1A, SMC3, RAD21 and stromalin and those that interact with the complex: NIPBL and HDAC8. The severity depends on the specific gene mutated and the more sever form of the diseases arises due to a mutation in NIPBL.
The most abundant form of CdLS arises due to either nonsense, splice site or frameshift mutations in NIPBL gene. The second most common form is a mutation of the SMC1A and SMC3 subunits of the cohesin complex. SMC1A/SMC3 mutations are less sever and arise from small insertion or deletions without frameshifts or missense mutations. There is a positive association between severity and commonality of CdLS in the population, this relationship can be witnessed by the level of chromatin decompaction in CdLS individuals. In the experiment conducted by Nolen L and et al, NIPBL and SMC3 were knocked down to observe the effects of chromatin decompaction. To reduce these proteins, siRNA was knocked down in fibrosarcoma cells followed by Fluorescence in situ hybridization to observe these changes. NIPBL knockdown showed significant levels of chromosome decompaction, while SMC3 knockdown showed no impacts. SMC3 was seen to alter the process of cohesion. Alteration in the dynamics does not necessarily lead to a malfunction in the phenotype. The unpredictable phenotype may or may not depict symptoms of CdLS, making it less common in the population than NIPBL which shows clear symptoms.
To investigate the phenotypic characteristics of NIPBL mutation in comparison to the mutated cohesin subunit, gene regulation was compared between NIPBL and RAD21. Individuals with CdLS demonstrate several phenotypic abnormalities. However, these abnormalities are more prominent in NIPBL mutated individuals than those with mutated RAD21. Wu Y and et al used an experiment to compare RNA levels present in NIPBL and RAD21. Initially, ribosomal RNA was depleted in a drosophila culture to reduce transcription in the cells. Afterwards, RNA sequencing was conducted to determine transcriptional activity followed by a comparison between the levels or RNA present in NIPBL and RAD21. They observed that RNA reduced by 27% in NIPBL mutation and 50% in RAD21 mutation. Therefore, they concluded that due to NIPBL having higher levels of RNA, it was able to express more genes that contributed to the phenotypic characteristics of CdLS. Therefore, due to RAD21 having phenotypic characteristics closer to the wild type, it is more difficult to detect the presence of mutation in a population resulting in it being less common than NIPBL mutation.
Therefore, when comparing the severity of mutations between NIPBL and those involved in the structural cohesion complex, it is seen that structural mutations have less sever phenotypic implications due to different gene regulation and impact on cohesion. Hence, due to there being more subtle differences in SMC1A/SMC3 and RAD21 the detection of these genes are less noticeable making them more less common in populations than NIPBL.