Genetics Of The GI - Cole Flashcards
Where does the aganglionic segment extend to in the short-segment form?
Long-segment?
Not beyond upper sigmoid
All the way to proximal to the sigmoid
What happens in hirschprungs?
Meissner’s and Myenteric plexus knocked out (results in clinical manifestation)
What is the clinical presentation of Hirschprung’s?
Intestinal obstruction, megacolon
Colon distention due to lack of peristalsis
What syndrome is most commonly associated with Hirschprung’s?
Who does it affect the most often?
Down syndrome
Males
What gene mutation is most commonly associated with Hirschsprung’s?
What protein function?
What frequency?
RET
Try Kinase receptor
70-80%, 50% familial, 15-20% sporadic
What kind of gene is the RET?
Where is it expressed?
GOF or LOF?
Proto-oncogene - regulates cell growth
Neural crest cells
LOF
What does the RET gene provide instructions for?
Without RET signaling, what does not develop properly?
Producing a protein that is involved in signaling within cells, including nerves in the intestine
Enteric nerves do not develop properly
What genes is responsible for hereditary hemochromatosis?
C282Y (92%)
H63D
What does AAT deficiency cause?
Jaundice and cirrhosis
How is iron transported?
Where is it stored?
Transferrin
Ferritin in liver and heart
How is it possible to get rid of iron?
Loss of enterocytes
Blood loss
Pregnancy
What can happen if too much iron is absorbed?
Tissue damage and fibrosis
What happens if too many erthrocytes are destroyed?
Accumulate in recticuloendothelial macrophages first
Tissue parenchyma after macrophages
What is secondary hemochromatosis due to?
Build of iron due to anemia, chronic liver disease, hep C, alcoholism, or frequent blood transfusions
Which genes are important for iron absorption regulation?
HFE, HJV, HAMP, TFR2
Which gene is responsible for regulating Hepcidin?
HAMP
What gene is responsible for most juvenile hemochromatosis?
HJV
Which gene is less common but with similar clinical presentations to the most common gene abnormality?
TFR2
What gene is responsible for the most common form of iron overload?
HFE
What is a protein involved in the uptake of transferrin-bound iron into cells?
Via what mechanism?
TFR2
endocytosis
What is an iron-binding blood plasma glycoproteins that controls the level of free iron in biological fluids?
Transferrin
What is a protein required for iron import from transferrin into cells?
Via what mechanism?
TFR1
Endocytosis
What protein functions to regulate circulating iron uptake by regulating the interaction of TFR1/2 with transferrin?
HFE
In Fe deficient states, describe Hepcidin and what is happening
Hepcidin low, ferroportin allows transfer of Fe from cells to blood
In Fe excess states, describe what hepcidin is doing
Hepcidin high, degrades ferroportin transporters
Mutations in what genes will result in low Hepcidin levels despite high iron levels?
HFE
HJV
TFR2
Describe the relationship between transferrin binding and TFR1, TFR2, and HFE
Transferrin prefers TFR2 > TFR1 > HFE
If HFE is unbound, what does this stimulate?
Hepcidin expression
When does onset of hemochromatosis begin? Later in who?
What symptoms?
Progresses to what?
Late onset (40s-50s), later in females
Non-specific symptoms
Hepatosplenomegaly
What is the one definitive sign of Hemochromatosis?
Iron Fist, pain in pointer and middle knuckle
What does intracellular iron lead to?
INC free radical production and peroxidation of phospholipids of mitochondria, lysosomes, microsomes
What does increased intracellular iron lead to?
Increased collagen synthesis -> fibrosis and cirrhosis
What is the treatment for hemochromatosis?
Therapeutic blood removal
Which group of people have an increased prevalence of hereditary hemochromatosis?
Is it homo or heterozygous?
Northern Europeans
EITHER ONE
Where is copper absorbed?
What is it bound to?
Where is it transported?
Stomach and duodenum
Albumin
Liver
What are the 2 genes involved in copper homeostasis?
ATP7A
ATP7B
Where is ATP7B located?
ATP7A?
Liver, brain, kidney, placenta
Most cells
What is the major copper-carrying protein in the blood?
Ceruloplasmin
What does Ceruloplasmin do to iron?
Oxidizes it, Fe2+ -> Fe3+
Which gene is mutated in Menkes syndrome?
What is the problem?
Clinical presentation?
ATP7A
Failure to absorb copper (uptake impaired)
Kinky, spiky, short, sparse, blonde hair, healthy for 2-3 months then dead by age 3
What additional clinical signs are associated with Menkes syndrome?
Vascular tortuosity
Laxity of skin
Occipital horns
What gene is mutated in Wilson’s disease?
What is the problem?
Clinical signs?
ATP7B
Failure to excrete copper (Cu cannot be released from hepatocytes)
Kayser-Fleischer ring around cornea, neurological disorders, psychiatric symptoms
What is the treatment for Wilson’s disease?
Menke’s Tx?
Copper chelation
Daily copper injection
What are the 2 forms of Hirschprung Disease?
Which is more prevalent?
Short and long-segment
Short-segment
