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Glycosylation, Hypogammaglobulinemia and Resistance to Viral

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by

Desmond Morris

on 6 May 2014

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Transcript of Glycosylation, Hypogammaglobulinemia and Resistance to Viral

Purpose
Materials & Methods
What is Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule
Summary
Two siblings with the rare genetic disorder
CDG-IIb
that causes severe hypogammaglobuinemia are paradoxically resistant to enveloped viral infection and transmission
Glycosylation, Hypogammaglobulinemia and Resistance to Viral Infections

By: Desmond Morris
Melody Kirby
Melody Clark

Authors
National Institute of Health
Mohammed A. Sadat, M.D., Ph.D., Susan Moir, Ph.D., Tae-Wook Chun, Ph.D., Paolo Lusso, M.D., Ph.D., Gerardo Kaplan, Ph.D., Lynne Wolfe, N.P., Matthew J. Memoli, M.D., Miao He, Ph.D., Hugo Vega, M.D., Ph.D.,
Leo J.Y. Kim, B.A., Yan Huang, Ph.D., Nadia Hussein, B.E., Elma Nievas, M.D., Raquel Mitchell, Ph.D., Mary Garofalo, R.N., Aaron Louie, B.Sc., Derek C. Ireland, Ph.D., Claire Grunes, Raffaello Cimbro, Ph.D., Vyomesh Patel, Ph.D.,
Genevieve Holzapfel, Ph.D., Daniel Salahuddin, B.Sc., Tyler Bristol, M.S., David Adams, M.D., Beatriz E. Marciano, M.D., Madhuri Hegde, M.D., Yuxing Li, Ph.D., Katherine R. Calvo, M.D., Ph.D., Jennifer Stoddard, B.S., J. Shawn Justement, M.S., Jerome Jacques, M.S., Debra A. Long Priel, M.S., Danielle Murray, M.A., Peter Sun, Ph.D., Douglas B. Kuhns, Ph.D., Cornelius F. Boerkoel, M.D., Ph.D., John A. Chiorini, Ph.D., Giovanni Di Pasquale, Ph.D.,
Daniela Verthelyi, M.D., Ph.D., and Sergio D. Rosenzweig, M.D., Ph.D.

What is CDG IIb?
Genetic defects in
MOGS
,the gene encoding
mannosyl-oligosaccaride glucosidase
causes the rare cogential disorder of glycosylation, CDG-IIb a neuro-degenerate disorder, which among other things causes severe
hypogammaglobuanemia

Hypogammaglobuinema
(HI-po-GAM-uh-GLOB-you-luh-NEE-mee-uh)
An abnormally low level of immunoglobins specifically IgG. Immunoglobins aka antibodies are proteins used to fight infections
Dysmorphic facial features
Hypotonia
seizures
global developmental delay
cerebral atrophy
small corpus callosum
optic nerve atrophy
sensorineural hearing loss\
hypoplastic genitalia
chronic constipation
recurrent bone fractures
severe hypogammaglobuninemia
Symptoms
UMM I missed Dr. Kim's class that day...


What do all those words mean?
Tests
Immunoblotting of Lysates
MALDI-TOF (Matrix assisted laser detection desorption ionization)
Enzyme Linked immunosorbent spot assay
Polymerase Chain Reaction Assay

The MOGS Gene
Located on the short P arm of chromosome 2
position 13.1 about 4500 bp in length
Results
Results
Results
Results
Why is this happening?
Patients show reduced ceceptibility to glycosylation dependent virons only
Data suggests that altered glycosylation might modify the suceptibility to infection to viruses that must undergo protien glycosylation to complete their infection cycle
Stands for mannosyl-oligosaccharide glucosidase
The purpose of this study was to investigate why two children with CDG-IIb with severe hypogammoglobulinemia are immune to certain types of viral infections



Future Direction
To study biological activity of CDG-IIb and immunoglobulins by evaluating
MOGS expression
Plasma IgG N-Glycan profile
Unfolded protein response and ER-associated degradation
in vitro imunoglobin production
immunoglobin half-life
Thanks for listening!
Further study on the effects of using the drug cantanosperimine on viral glycoproteins to reduce rate of viral replication
MOGS inhibitors used to slow replication of HIV, dengue, herpes, and hepatitis C viruses
Reason for absence of frequent, severe bacterial infections in both patients
References
Imperiali B, O'Connor SE (1999). "Effect of N-linked glycosylation on glycopeptide and glycoprotein structure". Curr Opin Chem Biol 3 (6): 643–9
Sadat, Mohammad A. "New England Journal of Medicine." Glycosylation, Hypogammaglobulinemia, and Resistance to Viral Infections. N.p.: n.p., 2014. N. pag. Web. 6 May 2014. <http://www.nejm.org/doi/pdf/10.1056/NEJMoa1302846>.
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