Genetics of GI disorders

Question 1

hirschprung disease 2 forms and most common one

Answer 1

1) short-segment form (80% of cases) aganglionic segment does not extend beyond upper sigmoid
2) long segment: aganglionic extends proximal to the sigmoid

Question 2

clinical presentation of hirschprung disease

Answer 2

colon distension from lack of peristalsis

• 70% isolated cases
• 12% assoiciated with DS
• M:F = 4:1

Question 3

gene mutated in hirschprungs disease and freq

Answer 3

RET gene 70-80% of cases
50% familial
20% sporadic

Question 4

where is RET gene expressed and what type of mutation is associated with it and hirschprungs

Answer 4

in NC cells, loss of function mutation

Question 5

function of RET gene

Answer 5

provides instructions for producing protein involved in signlaing within cells including nerves in intestine

-without this enteric nerves do not form properly

Question 6

where is iron stored and in what form

Answer 6

heart and liver in form of ferritin

Question 7

iron overload caused by what? (2)

Answer 7

1) too much iron is absorbed, iron deposited in liver, heart, endocrine issues—> tissue damage and fibrosis
2) too many erythrocytes destroyed, accumulation in reticuloendothelial macrophages first then tissue parenchyma (spleen, bone marrow, liver)

Question 8

secondary hemochromatosis is a build up of iron due to what

Answer 8

anemia, chronic liver diseases, often a result of hep C infection of alcoholism. frequent blood transfusions

Question 9

what gene is the most responsible for most common form of iron-overload? which gene for juvenile hemochromatosis?

Answer 9

• HFE

- HJV

Question 10

what gene is responsible for making hepcidin

Answer 10

HAMP

Question 11

factors that increase iron absorption

Answer 11

inadequate intake in diet, impaired absorption, celiac disease, hypoxia, anemia, GI bleeding

Question 12

factors responsible for decreasing iron absorption

Answer 12

regular blood transfusions, high iron diet, iron loading vitamins

Question 13

HFE function

Answer 13

regulates circulating iron uptake by regulating interaction of TFR1/2 with transferrin

Question 14

hepcidin secretion from the liver is regulated by what protein?

Answer 14

HFE, HJV,TFR2. mutations in these result in low hepcidin despite high iron levels and inappropriate continued transport of iron into the plasma

Question 15

what two proteins fight for binding on TFR1 and which binds better. results in what

Answer 15

transferrin and HFE, transferrin binds better this causes more free HFE elevation on cell surface which stimulates hepcidin expression

Question 16

too much Fe2+ causes more ____ to be produced than ___. transferrins bind more ___ which stimulates what.

Answer 16

TFR2, TFR1

TFR2, more hepcidin expression

Question 17

when Fe2+ is elevated hepcidin is elevated, by what 2 mechs

Answer 17

transferrin binds TFR2 which frees up HFE

TFR2 being produced stimulates hepcidin

Question 18

onset of hemochromatosis

Answer 18

late onset: 40s to 50s in males and a little later in females

Question 19

non specific early symptoms of hemochromatosis

Answer 19

fatigue, joint pain, erectile dysfunction, increased pigmentation

Question 20

progression of hemochromatosis

Answer 20

turns to hepatosplenomegaly, liver fibrosis and cirrhosis and endocrinopathies

Question 21

endocrinopathies related to hemochromatosis

Answer 21

hypogonadism, hypoparathyroidism, hypopituitarism, diabetes (decreased GLUT2)

Question 22

this symptom is only found in hemochromatosis

Answer 22

the iron fist, pain in knuckles of pointer and middle finger

Question 23

increased intracellular iron leads to what

Answer 23

increased free radical production and peroxidation of phospholipids of organelles: mitochond, lysosomes, microsomes
leads to cell degen, death, and increased collagen syn–> fibrosis and cirrhosis

Question 24

how do you find the transferrin-iron saturation percentage

Answer 24

Serum iron divided by total iron binding capacity X 100

TS should be around 25-35%

Question 25

hereditary hemochromatosis genetics gene involved

and population more prevelant

Answer 25

C282Y and northern europeans (italy, germany, sweden)

Question 26

2 genes involved in wilson’s and menkes syndrome

Answer 26

ATP7a and ATP7b

a: found in most cells
b: found in liver kidney placneta and brain

Question 27

ATP7B faciliitates incorporation of copper into ___ to yield ___ which is neccessary for what

Answer 27

apoceruloplasmin to yield ceruloplasmin

neccessary to carry copper protein in the blood and also has a role in iron metabolism

Question 28

what does ceruloplasmin promote with iron

Answer 28

promotes iron loading onto transferrin which only binds Fe2+, if you reduce Cu2+ then this leads to reduced Fe2+ transport and an increased attempt to increase Fe2+ absorption

Question 29

DMT1

CRT1

Answer 29

DMT1: brings in iron into intestinal cells on apical membrane
CRT1 located on basolateral and apical surface, Cu@+ can enter from blood and intestine where it binds proteins with a high affinity for copper
ATP7A and B are importantly associated

Question 30

menkes syndrome gene mutated and mechanism

Answer 30

ATP7A, so copper cannot move from intesinal mucosa into blood = Cu2+ deficiency

Question 31

menkes clinical presentation

Answer 31

healthy until 3 months, hypotonia, seizures, failure to thrive
diagnosis when infants exhibit typical neurologic changes and concomitant characteristic changes of hair
maybe hypoglycemia and temp instability, death usually occurs by 3 years of age
-vascular toruosity
-occipital horns
-laxity of skin

Question 32

what are the 2 ways to excrete copper?

Answer 32

1) excess copper induces metallothionein production in enterocytes which bind copper and these enterocytes shed
2) ceruloplasmin binds excess copper in liver and excreted with liver

Question 33

mutations in ______ gene prevent what in wilson disease

Answer 33

ATP7B prevent copper release from hepatocytes

• apoceruloplasmin is degraded without copper bound and ceruloplasmin levels decrease
• Fe2+/Fe3+ levels affected

Question 34

clinical presentation of wilson’s disease

Answer 34

neurologic symptoms, psychiatric symptoms and Kayser-Fleisher rings (copper deposition in descemet’s membrane of cornea)