Genetics of GI disorders Flashcards
hirschprung disease 2 forms and most common one
1) short-segment form (80% of cases) aganglionic segment does not extend beyond upper sigmoid
2) long segment: aganglionic extends proximal to the sigmoid
clinical presentation of hirschprung disease
colon distension from lack of peristalsis
- 70% isolated cases
- 12% assoiciated with DS
- M:F = 4:1
gene mutated in hirschprungs disease and freq
RET gene 70-80% of cases
50% familial
20% sporadic
where is RET gene expressed and what type of mutation is associated with it and hirschprungs
in NC cells, loss of function mutation
function of RET gene
provides instructions for producing protein involved in signlaing within cells including nerves in intestine
-without this enteric nerves do not form properly
where is iron stored and in what form
heart and liver in form of ferritin
iron overload caused by what? (2)
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)
secondary hemochromatosis is a build up of iron due to what
anemia, chronic liver diseases, often a result of hep C infection of alcoholism. frequent blood transfusions
what gene is the most responsible for most common form of iron-overload? which gene for juvenile hemochromatosis?
- HFE
- HJV
what gene is responsible for making hepcidin
HAMP
factors that increase iron absorption
inadequate intake in diet, impaired absorption, celiac disease, hypoxia, anemia, GI bleeding
factors responsible for decreasing iron absorption
regular blood transfusions, high iron diet, iron loading vitamins
HFE function
regulates circulating iron uptake by regulating interaction of TFR1/2 with transferrin
hepcidin secretion from the liver is regulated by what protein?
HFE, HJV,TFR2. mutations in these result in low hepcidin despite high iron levels and inappropriate continued transport of iron into the plasma
what two proteins fight for binding on TFR1 and which binds better. results in what
transferrin and HFE, transferrin binds better this causes more free HFE elevation on cell surface which stimulates hepcidin expression
too much Fe2+ causes more ____ to be produced than ___. transferrins bind more ___ which stimulates what.
TFR2, TFR1
TFR2, more hepcidin expression
when Fe2+ is elevated hepcidin is elevated, by what 2 mechs
transferrin binds TFR2 which frees up HFE
TFR2 being produced stimulates hepcidin
onset of hemochromatosis
late onset: 40s to 50s in males and a little later in females
non specific early symptoms of hemochromatosis
fatigue, joint pain, erectile dysfunction, increased pigmentation
progression of hemochromatosis
turns to hepatosplenomegaly, liver fibrosis and cirrhosis and endocrinopathies
endocrinopathies related to hemochromatosis
hypogonadism, hypoparathyroidism, hypopituitarism, diabetes (decreased GLUT2)
this symptom is only found in hemochromatosis
the iron fist, pain in knuckles of pointer and middle finger
increased intracellular iron leads to what
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
how do you find the transferrin-iron saturation percentage
Serum iron divided by total iron binding capacity X 100
TS should be around 25-35%
hereditary hemochromatosis genetics gene involved
and population more prevelant
C282Y and northern europeans (italy, germany, sweden)
2 genes involved in wilson’s and menkes syndrome
ATP7a and ATP7b
a: found in most cells
b: found in liver kidney placneta and brain
ATP7B faciliitates incorporation of copper into ___ to yield ___ which is neccessary for what
apoceruloplasmin to yield ceruloplasmin
neccessary to carry copper protein in the blood and also has a role in iron metabolism
what does ceruloplasmin promote with iron
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
DMT1
CRT1
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
menkes syndrome gene mutated and mechanism
ATP7A, so copper cannot move from intesinal mucosa into blood = Cu2+ deficiency
menkes clinical presentation
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
what are the 2 ways to excrete copper?
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
mutations in ______ gene prevent what in wilson disease
ATP7B prevent copper release from hepatocytes
- apoceruloplasmin is degraded without copper bound and ceruloplasmin levels decrease
- Fe2+/Fe3+ levels affected
clinical presentation of wilson’s disease
neurologic symptoms, psychiatric symptoms and Kayser-Fleisher rings (copper deposition in descemet’s membrane of cornea)
