This webpage was produced as an assignment for Genetics 564, an undergraduate capstone at University of Wisconsin- Madison
What is Severe Combined Immunodeficiency?
SCID is a primary immunodeficiency disorder causing a defective development of T-Lymphocytes and B-Lymphocytes, two major cellular components of the adaptive immune system. The lack of these vital components leaves the patient extremely susceptible to serious infections (1). 9 different gene mutations have been discovered to be a cause of SCID. The child will appear to look healthy & normal but with a severely compromised immune system, the patient will be extremely susceptible to severe bacterial, viral, or fungal infection (2).
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Figure[4] above shows David Vetter, a patient born in 1971 with SCID who was nicknamed "Bubble Boy" for his 12 years that he lived inside a sterilized bubble to prevent infection from air particle contact. David's own blood cells have paved the way for new therapies helping patients live full and normal lives [3].
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Genes of Interest
SCID has been linked to multiple causes and several gene defects that have potentially attributed to the genetic disorder. The main focus of this study is looking at 1 of the 8 main classifications of the disease, in particular, Adenosine Deaminase (ADA) deficiency. This is the second most common form of the disease which is caused by an ADA gene mutation on Chromosome 20 [7]. The mutation causes a deficiency in the ADA enzyme that normally functions to break down purines. The lack of the ADA gene causes an accumulation of deoxyadenosine triphosphate (dATP). This nucleotide accumulation inhibits the activity of the enzyme ribonucleotide reductase [7]. Without a functioning ribonucleotide reductase, ribonucleotides are not effectively generated into deoxyribonucleotides(dNTPs), the building blocks of new DNA structures. The immune system is dependant on lymphocyte proliferation which is dependent on dNTPs & without proliferation of lymphocytes it greatly compromises the immune system [7].
SCID has been linked to multiple causes and several gene defects that have potentially attributed to the genetic disorder. The main focus of this study is looking at 1 of the 8 main classifications of the disease, in particular, Adenosine Deaminase (ADA) deficiency. This is the second most common form of the disease which is caused by an ADA gene mutation on Chromosome 20 [7]. The mutation causes a deficiency in the ADA enzyme that normally functions to break down purines. The lack of the ADA gene causes an accumulation of deoxyadenosine triphosphate (dATP). This nucleotide accumulation inhibits the activity of the enzyme ribonucleotide reductase [7]. Without a functioning ribonucleotide reductase, ribonucleotides are not effectively generated into deoxyribonucleotides(dNTPs), the building blocks of new DNA structures. The immune system is dependant on lymphocyte proliferation which is dependent on dNTPs & without proliferation of lymphocytes it greatly compromises the immune system [7].
Figure [5] shows regional mapping of the
ADA gene located on the 20th Human chromosome. |
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Gene History
The discovery of ADA deficiency was discovered in two patients with cellular immune deficiency in 1972 by Dr. Eloise Giblett and colleagues during the era of molecular mechanism investigation underlying primary immunodeficiency disorders. In the era before gene pathology discovery , the only cure for severe immunodeficiency was a bone marrow transplant from a histocompatible donor. 1 of the 2 patients of Dr. Giblett, the typical HLA typing of family members led to no suitable donors. Isozyme patterns of the patient’s blood cells were run through a gel electrophoresis and was discovered that the red blood cells were completely lacking ADA enzyme activity. Dr Gibletts later concluded that “Since ADA anenzymia and the inherited diseases of cellular immunity are extremely rare, their coexistence in two unrelated patients seems very unlikely to be fortuitous.” [5].
Pattern of Inheritance
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Immune Deficiency Foundation
110 West Road, Suite 300 Towson, MD 21204 Phone: 800-296-4433 Fax: 410-321-9165 [email protected]. |
Save Babies Through Screening Foundation
P. O. Box 42197, Cincinnati, Oh 45242 Toll Free: 1-888-454-3383 Email: [email protected] |
Jeffrey Modell Foundation
780 Third Avenue New York, NY 10017 Fax: 212-764-4180 Email:i[email protected] |
National Organization for Rare Disorders
National Headquarters 55 Kenosia Avenue Danbury, CT 06810 Phone: 203-744-0100 Fax: 203-263-9938 |
References
[1] Immune Deficiency Foundation: Severe Combined Immunodeficiency & Combined Immune Deficiency. <https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency>
[2] Burg M, Gennery AR (2011). "Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency". Eur J Pediatr. 170: 561–571.
[3] Immune Deficiency Foundation: The Story of David. <https://primaryimmune.org/living-pi-explaining-pi-others/story-david>
[4] Houston Public Media: Tag David Vetter. <https://www.houstonpublicmedia.org/tag/david-vetter/>
[5] Blackburn, Michael R. Thompson, Linda F. “Adenosine deaminase deficiency: unanticipated benefits from the study of a rare immunodeficiency”. J Immunol. 2012
Feb 1; 188(3): 933–935.
[6] Merlin G. Butler, Syed K. Rafi and Ann M. Manzardo. "High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders." Int. J. Mol. Sci. 2015, 16(3), 6464-6495
[7] Adenosine Deaminase Deficiency More than just an Immunodeficicency https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985714/pdf/fimmu-07-00314.pdf
[8] Autosomal Recessive inheritance pattern
https://www.mayoclinic.org/autosomal-recessive-inheritance-pattern/img-20007457
[1] Immune Deficiency Foundation: Severe Combined Immunodeficiency & Combined Immune Deficiency. <https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency>
[2] Burg M, Gennery AR (2011). "Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency". Eur J Pediatr. 170: 561–571.
[3] Immune Deficiency Foundation: The Story of David. <https://primaryimmune.org/living-pi-explaining-pi-others/story-david>
[4] Houston Public Media: Tag David Vetter. <https://www.houstonpublicmedia.org/tag/david-vetter/>
[5] Blackburn, Michael R. Thompson, Linda F. “Adenosine deaminase deficiency: unanticipated benefits from the study of a rare immunodeficiency”. J Immunol. 2012
Feb 1; 188(3): 933–935.
[6] Merlin G. Butler, Syed K. Rafi and Ann M. Manzardo. "High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders." Int. J. Mol. Sci. 2015, 16(3), 6464-6495
[7] Adenosine Deaminase Deficiency More than just an Immunodeficicency https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985714/pdf/fimmu-07-00314.pdf
[8] Autosomal Recessive inheritance pattern
https://www.mayoclinic.org/autosomal-recessive-inheritance-pattern/img-20007457