Photo: Telophase Hela (cancer) cells expressing Aurora B-EGFP (green), Dr. Paul D. Andrews : University of Dundee
This webpage was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
This webpage was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is Cornelia de Lange Syndrome (CdLS)?
Cornelia de Lange Syndrome is a severe developmental disorder caused by mutations in cohesin structural or loading machinery. This website will focus on the NIPBL protein which loads a protein complex called cohesin onto DNA. Mutations in the NIPBL gene are responsibly for approximately 60% of CdLS cases [1]. Other proteins whose mutations often lead to CdLS are structural proteins in the cohesin complex. The CdLS phenotype is believed to be caused by a dysregulation in gene expression with one paper finding that 433 genes were differentially expressed in NIPBL mutants [9]. CdLS is characterized by craniofacial abnormalities, intellectual disabilities, skeletal abnormalities, growth retardation, and gastrointestinal, cardiovascular, eyesight, and hearing problems [1].
What is the cohesin complex?
Cohesin is multisubunit complex which mediates; cohesion between replicated sister chromatids, DNA repair, and gene regulation [9]. Cohesin is a conglomerate of different proteins which work together as one unit (cohesin) to manipulate chromatin structure. Cohesin is involved in a large number of cellular processes as chromatin remodeling, transcriptional regulation, DNA damage repair, and sister chromatid cohesion. Mutations in NIPBL then lead to a malfunctioning cohesin complex and the CdLS phenotype [6].
How is CdLS inherited?
CdLS is an autosomal dominant disease meaning that if one of the parents is affected the likelihood that a child will have the condition is 50 percent [1]. Although CdLS is highly heritable, 99 percent of CdLS cases are the result of de novo pathogenic variants [1]. It is also possible that the mutation was a result of germline mosaicism and not a de novo mutation. Germline mosaicism refers to a population of sex cells in one of the proband's (CdLS individual) parents that also has the mutation. Because of this germline mocaicism scenario the likelihood that the proband's parents next child is affected is not close to zero and is instead about 1.5% [7].
A Brief History of CdLS:
1849 : CdLS characteristics are initially described by Vrolik 4.
1916 : Dr. Winfried Robert Clemens Brachmann writes a report noting characteristics that are now associated with CdLS. 2. 1941 : Dr. Cornelia de Lange presents another case of CdLS to the Amsterdam Neurological Society and CdLS gains recognition as a diagnostic entity. 2. 2004 : Mutations in NIPBL are discovered to cause CdLS. 25. , 26. Present : New papers are published regularly further elucidating NIPBL’s role in disease etiology and the cell. |
A Crash-Course in DNA, genes, histones, and chromosomes:
DNA and genes
Deoxyribonucleic acid is found on all organisms on the planet and capable of mutagenesis. Mutations in DNA can occur for a variety of reasons: molecular-mechanical events (i.e. another protein shearing it), UV rays, bases spontaneously changing, transposable elements, and errors during the replication process. These mutations can lead to cancers, disorders, and new traits. It is also possible for mutations to have no physically observable (phenotypic) effect if the mutation is outside of a protein coding region (gene).
Histones
Histones are octa-meric proteins in which DNA is wrapped around. This organization makes the DNA more compact and allows for another layer of gene regulation.
Chromosomes
Histones and DNA is then wrapped upon itself two more times and then organized one more time into large cellular structures called chromosomes. Human somatic cells contain 46 chromosomes (23 unique chromosomes, each with a duplicate) and human sex cells contain 23 (no duplicates).
Deoxyribonucleic acid is found on all organisms on the planet and capable of mutagenesis. Mutations in DNA can occur for a variety of reasons: molecular-mechanical events (i.e. another protein shearing it), UV rays, bases spontaneously changing, transposable elements, and errors during the replication process. These mutations can lead to cancers, disorders, and new traits. It is also possible for mutations to have no physically observable (phenotypic) effect if the mutation is outside of a protein coding region (gene).
Histones
Histones are octa-meric proteins in which DNA is wrapped around. This organization makes the DNA more compact and allows for another layer of gene regulation.
Chromosomes
Histones and DNA is then wrapped upon itself two more times and then organized one more time into large cellular structures called chromosomes. Human somatic cells contain 46 chromosomes (23 unique chromosomes, each with a duplicate) and human sex cells contain 23 (no duplicates).
Support/ Donation Information
The Cornelia de Lange Foundation website.
http://www.cdlsusa.org/
World Federation of CdLS Support Groups
http://www.cdlsworld.org/xwiki/bin/view/Main/
http://www.cdlsusa.org/
World Federation of CdLS Support Groups
http://www.cdlsworld.org/xwiki/bin/view/Main/
References
1.Deardorff, Matthew, et al. Gene Reviews. University of Washington Seattle , 2016. NCBI, www.ncbi.nlm.nih.gov/books/NBK1104/.
2. CdLS Foundation. – Cornelia de Lange Syndrome Foundation,inc.
http://www.cdlsusa.org/about-cdls-foundation/our-history.htm
25. Krantz I. D., McCallum J., DeScipio C., Kaur M., Gillis L. A., Yaeger D., Jukofsky L., Wasserman N., Bottani A., Morris C. A., Nowaczyk M. J., Toriello H., Bamshad M. J., Carey J. C., Rappaport E., Kawauchi S., Lander A. D., Calof A. L., Li H. H., Devoto M., Jackson L. G. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat. Genet.(2004);36:631–635. doi: 10.1038/ng1364. [PMC free article] [PubMed] [Cross Ref]
26. Tonkin E. T., Wang T. J., Lisgo S., Bamshad M. J., Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet. (2004);36:636–641. doi: 10.1038/ng1363. [PubMed] [Cross Ref]
4.) Zhong, Qiulian, et al. “Mutation Analysis in Chinese Patients with Cornelia De Lange Syndrome.” Genetic Testing and Molecular Biomarkers, vol. 16, no. 9, Sept. 2012, pp. 1130–1134. NCBI, doi:10.1089/gtmb.2011.0383.
6.) Strachan, Tom. “Cornelia De Lange Syndrome and the Link between Chromosomal Function, DNA Repair and Developmental Gene Regulation.” Current Opinion in Genetics & Development, vol. 15, no. 3, 2005, pp. 258–264., doi:10.1016/j.gde.2005.04.005.
7.) Jackson L, Kline AD, Barr MA, Koch S. de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet. 1993;47:940–6
8.) Retrieved April 12, 2018, from https://www.ncbi.nlm.nih.gov/protein/NP_597677.2
NCBI Protein database, NCBI Reference Sequence: NP_597677.2
9.) Peters, J., Tedeschi, A., & Schmitz, J. (2008). The cohesin complex and its roles in chromosome biology. Genes and Development,3089-3114. doi:10.1101/gad.1724308
10.) Mills, J., Herrera, P., & Kaur, M. et al. (2018). NIPBL /− haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states. Scientific Reports. doi:doi:10.1038/s41598-018-19173-9
2. CdLS Foundation. – Cornelia de Lange Syndrome Foundation,inc.
http://www.cdlsusa.org/about-cdls-foundation/our-history.htm
25. Krantz I. D., McCallum J., DeScipio C., Kaur M., Gillis L. A., Yaeger D., Jukofsky L., Wasserman N., Bottani A., Morris C. A., Nowaczyk M. J., Toriello H., Bamshad M. J., Carey J. C., Rappaport E., Kawauchi S., Lander A. D., Calof A. L., Li H. H., Devoto M., Jackson L. G. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat. Genet.(2004);36:631–635. doi: 10.1038/ng1364. [PMC free article] [PubMed] [Cross Ref]
26. Tonkin E. T., Wang T. J., Lisgo S., Bamshad M. J., Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet. (2004);36:636–641. doi: 10.1038/ng1363. [PubMed] [Cross Ref]
4.) Zhong, Qiulian, et al. “Mutation Analysis in Chinese Patients with Cornelia De Lange Syndrome.” Genetic Testing and Molecular Biomarkers, vol. 16, no. 9, Sept. 2012, pp. 1130–1134. NCBI, doi:10.1089/gtmb.2011.0383.
6.) Strachan, Tom. “Cornelia De Lange Syndrome and the Link between Chromosomal Function, DNA Repair and Developmental Gene Regulation.” Current Opinion in Genetics & Development, vol. 15, no. 3, 2005, pp. 258–264., doi:10.1016/j.gde.2005.04.005.
7.) Jackson L, Kline AD, Barr MA, Koch S. de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet. 1993;47:940–6
8.) Retrieved April 12, 2018, from https://www.ncbi.nlm.nih.gov/protein/NP_597677.2
NCBI Protein database, NCBI Reference Sequence: NP_597677.2
9.) Peters, J., Tedeschi, A., & Schmitz, J. (2008). The cohesin complex and its roles in chromosome biology. Genes and Development,3089-3114. doi:10.1101/gad.1724308
10.) Mills, J., Herrera, P., & Kaur, M. et al. (2018). NIPBL /− haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states. Scientific Reports. doi:doi:10.1038/s41598-018-19173-9