Congenital Disorders of Glycosylation Flashcards
Name the two types of glycosylation.
N-glycosylation
O-glycosylation
What is N-glycosylation?
glycosylation of proteins via the amide group of asparagine in the ER (begins assembly on ER wall in cytoplasm and “flips” into ER when chain gets long/heavy enough) –> when 14 sugars are achieved it exports to the ribosome complex –> terminal glucose and manose removed –> transfer to the Golgi for pruning
What are the functions of N-glycan proteins?
protein folding and stability protein-protein complex formation imparting protease resistance signaling cell-cell recognition
What are COGs?
Concerved Oligomeric Golgi Complex
permanent Golgi proteins that are involved in retrograde vesicle tethering
8 subunits organized into two lobes
What is O-glycosylation?
glycosylation of proteins via OH group of serine or threonine
What are the functions of O-glycan proteins?
antibacterial agent in saliva
defines ABO blood type
involved in sperm motility, sperm-egg binding, and preventing of polyspermia
cell adhesion and migration
lymphocyte targeting and inflammatory response
Which conditions cause abnormal processing in the Golgi?
CDG-IIa (MGAT2) CDG-IIb (GCS1) CDG-IIc (SLC35C1) CDG-IId (B4GALT1) CDG-IIe (COG7) CDG-IIf (LEC2) CDG-IIg (COG1) CDG-IIh (COG8)
Describe the inheritance of CDGs.
X-linked: MAGT1-CDG, SSR4-CDG, PIGA-CDG, and SLC35A2-CDG
AD (disorders due to loss of function –> haploinsufficiency): EXT1-CDG and EXT2-CDG
All the rest are AR
(De novo mutations normally cause AD XL ALG13-CDG and SLC35A2-CDG
What is CDT testing?
carbohydrate deficient transferrin testing
transferrin is glycosylated by N-glycosylation
Type I defects caused by sialic acid not added to the carbohydrate chain (increased bands of disialotransferrin and asialotransferrin on isoelectric focusing)
Type II defects caused by carbohydrate chains that are too broken up (increased bands of trisialotransferrin and monosialotransferrin on isoelectric focusing)
cannot pick up O-glycosylation defects
What is tandem mass spec testing used for in errors of glycosylation?
divides particles by charge and mass to give you a picture of the structure of the protein
if you do not have a peak at the normal places you will see which parts are missing/affected by the mutation
What testing options are available for the diagnostic workup of a patient suspected to have an error of glycosylation?
abnormal glycosylation testing pattern (transferrin for patients older than three weeks and Apo-C)
enzyme analysis
DNA testing (NGS, WES, WGS)
What is PMM2-CDG?
phosphomannomutase deficiency caused by defects in the CDGIa gene
neonatal presentation (ususal): inverted nipples, poor feeding, abnormal fat distribution, hypotonia, cardiac, manifestations (pleurocardial effusion), strabismus (lazy eyes)
later organ involvement: hepatic fibrosis with hepatomegally, nephrosis, gonadal failure
thrombotic events may be seen with reduced factor XI, protein C, and ATIII
neurodevelopmental issues and seizures with abnormal brain findings
abnormal transferrin testing (Type I)
symptomatic treatment
What is PMI-CDG?
mannose-6-P isomerase deficiency caused by defects in the CDGIb gene
main manifestations: GI (emesis, chronic diarrhea, protein losing enteropathy, FTT, hepatic fibrosis), may develop hyperinsulinemia, hypoglycemia, and coagulation disturbances
no dysmorphism or neuro manifestations unless there is a stroke
treat with mannose (large amounts)
What is ATP6V0A2-CDG?
AR cutis laxa
mainly presents with loose wrinkly skin and large fontanelles
elastin fibers are not glycosylated, so the connective tissue is weakened
can be detected on CDT testing (Type II)
What is COG7-CDG?
alters golgi trafficking –> glycosyltransferase activity
presents with microcephally, failure to thrive, adducted thumbs, VSD, hyperthermia