Discussion: Treacher Collins Syndrome
Discussion: Treacher Collins Syndrome
Discussion: Treacher Collins Syndrome
Based on the Reading & Study materials for this module/week, reply to the reviews of at least 2 of your classmates by offering a critique of the animal model. If an animal model exists for this disease or disorder, critique whether it is a reasonable model of the disease (does it truly model the human condition?). If none exists, propose which organism you would select as a model and explain why. each reply should be 250 word
first post
Golgi body and I-cell disease
Golgi disorders do cause the malfunction of the secretory paths of the rough endoplasmic reticulum, protein secretion and synthesized packaging, such as I-cell disease, which is also known as mucolipidosis II. Lysosomes secreted is a result of Golgi body failure to phosphorylate properly and sort proteins in a required way thus causing I-cell disease. Yokoi et al. (2019) described that patients diagnosed with this disease they are familiar with facial and skeletal abnormalities characteristics.
I-cell sickness may establish at birth as rough characteristics, organomegaly, retinal clouding, hypertonia, and chronic inflammation of the gingiva. Frequently, the weight and duration of the conception are all below normal. Lumbar gibbus, Kyphoscoliosis and limited mobility of the joints are always present, and hip dislocation, hernias, fractures or bilateral equinovaric disease – causing gene may appear. Dysostosis multiplex could be seen on radiographs (Wang, Mazrier, Rae, Raj & Giger, 2018). Severe psychomotor retardation, apparent at the age of 6 months, and gradual failure to thrive are present. Facial characteristics are soft with a big forehead, epicanthic folds, eyelids which are puffy, nasal bridge which is flat, macroglossia and nares which are anteverted. Linear growth slows and eventually stops completely the skeletal involvement during the first years of life, with increased joint immobility and claw hand defects. With bacterial illnesses, otitis media and cardiac involvement, complications are prevalent. During the first 5 years of life, death is caused by cardiorespiratory complications.
It is possible to produce an I-cell phenotype in other theoretical ways. In Trans-Golgi, the uncovering enzyme (N-acetyl glucosamine 1-phosphodiester alpha-N-acetyl glucosaminidases) must function to eliminate the residue of glucosamine that uncovers the composition of mannose 6-phosphate to reveal the specific target signal of mannose 6-phophate (Ramesh, Susitna, Leslie & Jayashree, 2017). A defect in the enzyme activity may result in an abnormality related to the classical I-cell illness, centered on the incapability of MPR to identify a 6-phosphate frequency targeting mannosis. This could give rise to a similar outcome to the cumulative MPR mutation that, as defined in an experimental animals below, results in an I-cell-like gene. Golgi-localized γ-containing ADP ribosylation key element proteins necessary for MPR mobility could be involved in other possible faults that lead to an I-cell-like trait. This can lead to similar pathologies because it is not able to distribute lysosome enzymes from trans-Golgi to the endosome lysosome system.
References
Singh, A., Prasad, R., Gupta, A. K., Sharma, A., Alves, S., Coutinho, M. F., … & Mishra, O. P. (2017). I Cell disease (mucolipidosis II alpha/beta): from screening to molecular diagnosis. The Indian Journal of Pediatrics, 84(2), 144-146.
Yokoi, A., Niida, Y., Kuroda, M., Imi-Hashida, Y., Toma, T., & Yachie, A. (2019). B-cell-specific accumulation of inclusion bodies loaded with HLA class II molecules in patients with mucolipidosis II (I-cell disease). Pediatric research, 86(1), 85-91.
Wang, P., Mazrier, H., Rae, J. C., Raj, K., & Giger, U. (2018). BMC veterinary research, 14(1), 1-8.
Ramesh, B., Susmitha, T., Leslie, L., & Jayashree, P. (2017). I-Cell Disease with GNPTAB Gene Mutation. International Journal of Pediatrics, 5(12), 6261-6265.
example of reply:I hope that all is well. Thank you for your discussion post. It was very informative. However, I don’t believe you specifically identified an animal that is used for this I-cell disease. While researching this disease, I read that an animal model that has been used for I-cell disease is short hair cats. The clinical features of the affected cat were very similar to human patients with I-cell disease. These clinical features include behavioral dullness, ataxia, dysostosis multiplex, and even early death (1). The affected cats with I-cell disease had retinal degeneration leading to blindness by the age of four months. This does not affect human patients.
Also, I researched the prevalence of I-cell disease because this is my first time hearing about this disease. The prevalence of this disease is about 1 in 100,000-400,000 (2). Therefore, this disease is rare. The symptoms of golgi-linked diseases are retardation, liver disease, and seizures. Overall, your discussion board post was very informative!
Good luck during these 8 weeks!
References:
1. Brooks D., Turner C., Muller V., Hopwood J.J., Meikle P. (2007) I-Cell Disease. In: Lysosomal Storage Disorders. Springer, Boston, MA.
2. Edmiston, R., Wilkinson, S., Jones, S., Tylee, K., Broomfield, A., & Bruce, I. A. (2019). I-Cell Disease (Mucolipidosis II): A Case Series from a Tertiary Paediatric Centre Reviewing the Airway and Respiratory Consequences of the Disease. JIMD reports, 45, 1–8.
Second post:
Treacher Collins syndrome is a ribosomopathy-related disorder. It is caused by genetic mutations, which are most often de novo in nature. Signs such as craniofacial deformities such as an underdeveloped jaw, zygomatic arch, palate, and external and middle ear abnormalities characterize this disorder.
Also, a patient with Treacher Collins syndrome may present with downward slanted eyes. While the characteristics above are cosmetic, individuals with this disorder may suffer from hearing loss, dysphagia, and difficulty breathing, all secondary to the above deformations. In some cases, behavior abnormalities occur.
Individuals with cosmetic abnormalities alone usually will have the same life expectancy as an unaffected individual. Treacher Collins syndrome’s most severe effect is the potential for breathing and feeding challenges in the affected infant with an underdeveloped or malformed palate. However, in most countries, a plastic surgeon can reform the palate, eliminating the disease’s fatal features.
De novo genetic mutations specifically in the POLR1- genes cause the creation of faulty ribosomes. Ribosomes are responsible for transcribing RNA in conjunction with polymerases I and III. In functional ribosomes, this leads to protein synthesis within the cell and is directly related to cell generation and differentiation.
In Treacher Collins syndrome, abnormalities can be found in neural crest cells and Tp53-dependent neuroepithelial cells secondary to flawed production by the ribosomes. These two cell types are responsible for creating craniofacial bone and cartilage—amongst other responsibilities—during early fetal growth stages. When they are malformed, they lead to the symptoms seen in Treacher Collins syndrome: craniofacial deformations. Discussion: Treacher Collins Syndrome
An interesting proposed treatment option is the intentional inhibition of Tp53 during embryonic growth to limit the neuroepithelial cells’ malformation. Tp53 inhibition may lead to reduced craniofacial deformities as the fetus develops features. However, Tp53 plays a role in tumor suppression. Therefore, if Tp53 were intentionally inhibited, the risk of tumor growth in the affected individual would increase exponentially. While Tp53 inhibition appears to be a reasonable Treacher Collins syndrome treatment method in theory, this method’s cons could prove to outweigh the pros. Discussion: Treacher Collins Syndrome
A zebrafish model experiment was conducted by altering the POLR1B gene in one study, and in another, POLR1C and POLR1D genes were altered. In both studies, Treacher Collins syndrome symptoms appeared in the zebrafish. The pattern leads one to conclude that mutations of the POLR1 gene’s different subunits (i.e., A, C, D) typically lead to ribosomopathy, which causes Treacher Collins syndrome or similar disorders.
To summarize, Treacher Collins syndrome is characterized by many craniofacial abnormalities ranging from cosmetic-only ear deformity to life-threatening palate deformity. A plastic surgeon can reconstruct a deformed palate to improve life expectancy and improve facial appearance through the use of implants and fillers. The disorder is caused by POLR1A, POLR1C, or POLR1D mutation (confirmed by zebrafish model) that impairs ribosomes’ ability to create functional Tp53-dependent neuroepithelial and neural crest cells. The poor cell formation leads to the above deformations during fetal development. Tp53 inhibition is proposed as a treatment option; however, it may not come to fruition as this would also stop the vital tumor inhibition function of Tp53.
Bowen, M. E., & Attardi, L. D. (2019). The role of p53 in developmental syndromes. Journal of Molecular Cell Biology, 11(3), 200-211. 10.1093/jmcb/mjy087
Elodie Sanchez, MLT, Béryl Laplace-Builhé, Frédéric Tran Mau-Them, Eric Richard, Alice Goldenberg, Tomi L. Toler, MS, Thomas Guignard, Vincent Gatinois, PharmD, Marie Vincent, Catherine Blanchet, Anne Boland, Marie Thérèse Bihoreau, MLT, Jean-Francois Deleuze, Robert Olaso, Walton Nephi, . . . David Geneviève. (2020). POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Nature Publishing Group. 10.1038/s41436
Sayyadi, S., Moghadam, M. J., Mirkheshti, A., Memary, E., Abtahi, D., Salimi, S., & Tajbakhsh, A. (2018). Treacher Collins Syndrome; Anesthetic considerations and Molecular Findings. Journal of Cellular & Molecular Anesthesia, 3(1), 31-34. 10.22037/jcma.v3i1.19790
Treacher Collins syndrome. Medline Plus.
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