Genetics Of The GI - Cole

Question 1

Where does the aganglionic segment extend to in the short-segment form?

Long-segment?

Answer 1

Not beyond upper sigmoid

All the way to proximal to the sigmoid

Question 2

What happens in hirschprungs?

Answer 2

Meissner’s and Myenteric plexus knocked out (results in clinical manifestation)

Question 3

What is the clinical presentation of Hirschprung’s?

Answer 3

Intestinal obstruction, megacolon

Colon distention due to lack of peristalsis

Question 4

What syndrome is most commonly associated with Hirschprung’s?

Who does it affect the most often?

Answer 4

Down syndrome

Males

Question 5

What gene mutation is most commonly associated with Hirschsprung’s?

What protein function?

What frequency?

Answer 5

RET

Try Kinase receptor

70-80%, 50% familial, 15-20% sporadic

Question 6

What kind of gene is the RET?

Where is it expressed?

GOF or LOF?

Answer 6

Proto-oncogene - regulates cell growth

Neural crest cells

LOF

Question 7

What does the RET gene provide instructions for?

Without RET signaling, what does not develop properly?

Answer 7

Producing a protein that is involved in signaling within cells, including nerves in the intestine

Enteric nerves do not develop properly

Question 8

What genes is responsible for hereditary hemochromatosis?

Answer 8

C282Y (92%)

H63D

Question 9

What does AAT deficiency cause?

Answer 9

Jaundice and cirrhosis

Question 10

How is iron transported?

Where is it stored?

Answer 10

Transferrin

Ferritin in liver and heart

Question 11

How is it possible to get rid of iron?

Answer 11

Loss of enterocytes
Blood loss
Pregnancy

Question 12

What can happen if too much iron is absorbed?

Answer 12

Tissue damage and fibrosis

Question 13

What happens if too many erthrocytes are destroyed?

Answer 13

Accumulate in recticuloendothelial macrophages first

Tissue parenchyma after macrophages

Question 14

What is secondary hemochromatosis due to?

Answer 14

Build of iron due to anemia, chronic liver disease, hep C, alcoholism, or frequent blood transfusions

Question 15

Which genes are important for iron absorption regulation?

Answer 15

HFE, HJV, HAMP, TFR2

Question 16

Which gene is responsible for regulating Hepcidin?

Answer 16

HAMP

Question 17

What gene is responsible for most juvenile hemochromatosis?

Answer 17

HJV

Question 18

Which gene is less common but with similar clinical presentations to the most common gene abnormality?

Answer 18

TFR2

Question 19

What gene is responsible for the most common form of iron overload?

Answer 19

HFE

Question 20

What is a protein involved in the uptake of transferrin-bound iron into cells?

Via what mechanism?

Answer 20

TFR2

endocytosis

Question 21

What is an iron-binding blood plasma glycoproteins that controls the level of free iron in biological fluids?

Answer 21

Transferrin

Question 22

What is a protein required for iron import from transferrin into cells?

Via what mechanism?

Answer 22

TFR1

Endocytosis

Question 23

What protein functions to regulate circulating iron uptake by regulating the interaction of TFR1/2 with transferrin?

Answer 23

HFE

Question 24

In Fe deficient states, describe Hepcidin and what is happening

Answer 24

Hepcidin low, ferroportin allows transfer of Fe from cells to blood

Question 25

In Fe excess states, describe what hepcidin is doing

Answer 25

Hepcidin high, degrades ferroportin transporters

Question 26

Mutations in what genes will result in low Hepcidin levels despite high iron levels?

Answer 26

HFE HJV TFR2

Question 27

Describe the relationship between transferrin binding and TFR1, TFR2, and HFE

Answer 27

Transferrin prefers TFR2 > TFR1 > HFE

Question 28

If HFE is unbound, what does this stimulate?

Answer 28

Hepcidin expression

Question 29

When does onset of hemochromatosis begin? Later in who? What symptoms? Progresses to what?

Answer 29

Late onset (40s-50s), later in females Non-specific symptoms Hepatosplenomegaly

Question 30

What is the one definitive sign of Hemochromatosis?

Answer 30

Iron Fist, pain in pointer and middle knuckle

Question 31

What does intracellular iron lead to?

Answer 31

INC free radical production and peroxidation of phospholipids of mitochondria, lysosomes, microsomes

Question 32

What does increased intracellular iron lead to?

Answer 32

Increased collagen synthesis -> fibrosis and cirrhosis

Question 33

What is the treatment for hemochromatosis?

Answer 33

Therapeutic blood removal

Question 34

Which group of people have an increased prevalence of hereditary hemochromatosis? Is it homo or heterozygous?

Answer 34

Northern Europeans EITHER ONE

Question 35

Where is copper absorbed? What is it bound to? Where is it transported?

Answer 35

Stomach and duodenum Albumin Liver

Question 36

What are the 2 genes involved in copper homeostasis?

Answer 36

ATP7A | ATP7B

Question 37

Where is ATP7B located? ATP7A?

Answer 37

Liver, brain, kidney, placenta Most cells

Question 38

What is the major copper-carrying protein in the blood?

Answer 38

Ceruloplasmin

Question 39

What does Ceruloplasmin do to iron?

Answer 39

Oxidizes it, Fe2+ -> Fe3+

Question 40

Which gene is mutated in Menkes syndrome? What is the problem? Clinical presentation?

Answer 40

ATP7A Failure to absorb copper (uptake impaired) Kinky, spiky, short, sparse, blonde hair, healthy for 2-3 months then dead by age 3

Question 41

What additional clinical signs are associated with Menkes syndrome?

Answer 41

Vascular tortuosity Laxity of skin Occipital horns

Question 42

What gene is mutated in Wilson's disease? What is the problem? Clinical signs?

Answer 42

ATP7B Failure to excrete copper (Cu cannot be released from hepatocytes) Kayser-Fleischer ring around cornea, neurological disorders, psychiatric symptoms

Question 43

What is the treatment for Wilson's disease? Menke's Tx?

Answer 43

Copper chelation Daily copper injection

Question 44

What are the 2 forms of Hirschprung Disease? Which is more prevalent?

Answer 44

Short and long-segment Short-segment