Disorders Affecting the GI system - Genetics Flashcards
Which disease is known to be a neurocristopatholgy where aberration in neural growth, migration and differentiation of neural crest cells during embryological development is the cause of the disease.
Hirschprung disease
In short-segment form of Hirschprung disease, the agnaglionic segment is limited to what location?
to the sigmoid and rectum. Not does extend beyond the upper sigmoid. this is also the 80% of cases of the disease
The Hirschprung disease, which plexuses is missing, myenteric or submucosal?
Both are missing. but it’s the myenteric that gives it the name megacolon
What is the clinical presentation of Hirschprung disease?
- intestinal obstruction -> megacolon
- Colon distention due to lack of peristalsis
- variability depends on region affected
Which congenital syndrome is most commonly associated with Hirshprung disease?
Down syndrome - about 12%
In what gender is Hirshprung more common in?
Male. it’s a 4:1 ratio
What gene mutation is associated with Hirshprung disease?
RET
WHat role does RET play at a molecular level?
It’s a tryrosine kinase receptor
In terms of cell cycle and growth, RET is is a _.
proto-oncogne which code for proteins that help regulate cell growth
For RET mutation, is it the gain of function or loss of function of the gene that leads to Hirshprung disease?
Loss of function. Without RET working, it can act as a tyrosine kinase receptor in the neural crest cells and thus cells are arrested
What role does the RET gene play in cell signaling?
RET gene provides instructions for producing a protein that is involved in signaling within cells, including nerves in the intestine.
What protein transports iron and what molecule is responsible for storing iron commonly in the liver and heart?
Transferrin transports
Ferritin stores.
What physiological mechanism excrete iron from the body?
There is no physiological mechanism for excreting iron. Few ways iron can be excreted include: enterocyte shedding, menses, pregnancy.
What does it mean by too much iron overload as seen in hemochromatosis?
It means iron in excess of transferrin binding capacity. The excess iron is deposited in liver, heart, and some endocrine tissues.
What are some secondary hemochromatosis causes?
Anemia, chronic liver disease (eg. hep C), infection, alcoholism, frequent blood transfusion. Not genetics.
Which gene mutation is the most common cause of HH?
HFE
The gene HJV is responsible for what type of hemochromatosis?
Responsible for most cases of juvenile hemochromatosis.
Mutation in HAMP gene can also need to hemochromotosis. What role does HAMP play?
HAMP is a gene responsible for hepcidin which is a iron-regulating hormone critical for absorption
The enterocytes normally are very good at regulating how much iron it lets into the body, due to mutation in this gene, that regulatory capacity of enterocytes are lost. What gene is that?
HFE.
What are some factors that will increase iron absorption?
- inadequate diet
- impaired absorption
- celiac disease
- GI bleeding
- anemias, decreased erythropoiesis
- hypoxia
What is the role of HFE protein on the enterocyte?
It regulate circulating iron uptake by regulating the interaction of TFR 1/2 with transferrin.
What is the role of TFR1/2?
TFR1: protein required for iron import from transferrin into cells by endocytosis.
TFR2: Protein involved in the uptake of transferrin-bound iron into the cells by endocytosis, although its role is minor compared to TFR1.
What is the role of hepcidin?
It is a key regulator of the entry of iron into the circulation
What is the role of transferrin?
It is a iron-binding blood plasma glycoprotein that controls the level of free iron in biological fluids
What is the role of ferroportin, and what inhibits it?
It is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell i.e. to the blood. It is inhibited by hepcidin, results in the retention of iron.
Explain what happens to hepcidin, and ferroportin during iron deficiency, and during iron overload?
During low iron, Hepcidin levels go down and ferroportin is then able to bring iron from enterocyte to blood. During iron overload, hepcidin levels increase and it internalizes ferroportin and breaks it down as a result iron is not able to enter the blood.
How does mutation in HFE, HJV or TFR2 effect hepcidin level?
Mutation results in low hepcidin levels despite high iron levels and inappropriate continued transport of iron into the plasma.
During high levels of iron, Transferrin and HFE compete for binding sites at which receptor and who wins?
TFR1 receptor on hepatocyte and other cells. Transferrin wins because it has a higher affinity.
elevated unbound HFE on cell surface stimulates expression of what?
Hepcidin
When theres too much Fe2+, it cause TFR2 to be produced more than TFR1. TFR2 binding of Fe2 + stimulates expression of what?
Hepcidin
In iron regulation the ultimate action of hepcidin is to _.
down regulate transport of Fe out of enterocytes.
In iron deficiency, there are is more bound HFE to transferrin which leads to decreased TFR2 receptors.. This results in decreased expression of what protein?
HAMP. This leads to decreased hepcidin and thus leading to increased Fe2+ transfer out of enterocytes.
What are clinical signs and symptoms of hemochroatosis?
- Early non-specific symptoms like fatigue, arthralgia, ED, increased pigmentation
- Progresses to hepatospelnomegaly
- increased liver damage leading to caricinoma
- ENdorincopathies: diabetes, hypopituitarism, hypogonadims, hypoparathyroidism
In hemochromatosis, destruction of islet cells of the pancreas leads to _.
Diabetes mellitus leading to decreased insulin to decreased GLUT 2
Bronze skin, iron fist sign, are characterisitic of what disease?
hemochromatosis
At a cellular level, explain why hemochromatosis cause damage?
with increased increased iron, there’s more activity of Fe2+ converting to Fe3+ and back to Fe 3+. every time it does than it creates free radical. Free radicals and peroxidation of phospholipids causes organelle damage (mt, lysosome, microsomes). with cell death, there’s more enzymes, and liver enzymes and increased collagen syntehsis leading to fibrosis and cirrhosis.
What blood tests can be obtained to diagnose hemochromotosis?
Serum iron, serum ferritin and total iron binding capacity.
What is the most common ways of decreasing iron levels and is used as a treatment option for hemochromotosis?
Phlebotomy.
A patient is diagnosed with hemochromotosis, how can you tell if its the hereditary form?
Check for mutation of C282Y where cys is replaced with TYR and also if the patient has an northern european ancestery.
Once copper is absrobed in the stomach and duodenum, how does it get to the liver?
Copper binds to albumin the serum and is carried to the liver.
What is the primary copper carrying protein in the blood?
Ceruloplasmin = 90% albumin = 10%
Cerulopasmin also plays a role in iron absorption, how?
Ceruloplasmin is an iron oxidoreductase which is important in iron absorption Fe2+ to Fe3+.
Transferrin can only bind what form of isotype of iron and what plasma protein helps to get it to that form?
Transferrin can only bind Fe+2. Ceuloplasmin can convert Fe+3 into Fe+2.
What two transporter are located on the apical and basolateral surfaces of enterocyte that which are important in copper absorption?
DMT1
CRT1
What gene is mutated in Menkes syndrome?
ATP7A
What is the normal function of ATP7A?
Move Cu from intestinal mucosa into the blood
What happens if ATP7A is mutated?
Uptake of Cu is impaired leading to Cu2+ deficiency. And because Cu acts as a cofactor in many reactions, those reactions cannot take place leading to a whole host of loss of physiological reactions.
What are some clinical presentation of Menkes syndrome?
Infants: healthy until age 2 or 3 then loss of developmental milestone, hypotonia, seizures, and failure to thrive. Infants will exhibit typical neurologic changes and concomitant characterisitic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented). Temp instability and hypoglycemia. Death by three years of age.
A infant presents with steel wool like hair, and has severe loss of developmental milestone, vascular tortuosity on MRI, and laxity of skin. What is the most likely diagnosis?
Menkes syndrome.
What gene is mutated in wilson’s disease?
ATP7B
What transporter carries copper from the lumen of small intestine to the enterocytes?
Copper membrane transporter 1 (CMT1)
What are two ways cupper can be excreted?
- Cu bound to metallothionein in enterocytes and then enterocytes shedding.
- Ceruloplasmin binds excess cu in the liver and is excreted out with bile.
With ATP7B mutation, how is Cu levels affected?
With mutation in ATP7B, Cu is prevented from being released from hepatocytes. ATP7B mutation causes degradation of apoceruloplasmin and so ceruloplasmin levels decrease.
How does Wilson’s disease present clinically?
- Progressive lenticular degeneration –> neurological effects.
- liver cirrhosis due to access copper.
What are some symptoms of wilson’s disease?
- Neurologic symptoms: movement disorder (tremors, poor coordination, loos of ifne-motor control, chorea,)
- Psychiatric symptoms: depression, neurotic behaviors, disorganziation of personality, intellectual deteroiation
- Kayser-Fleischer rings: copper deposition in descement’s membrane of the cornea.
