Genetics - Cole Flashcards
Etiology of Hirschsprung disease
abnormal neural growth, migration, and differentiation
Short segment form of Hirschsprung disease
does not extend beyond upper sigmoid
Long segment form of Hirschsprung disease
extends proximal to sigmoid
Clinical presentation of Hirschsprung disease
megacolon, lack of colon peritalsis
What other syndrome is commonly associated with Hirschsprung disease
Down syndrome
Who is Hirschsprung disease most common in (incidence)
male and asians
Most common gene associated with Hirschsprung disease
RET gene
Mode of inheritance for Hirschsprung disease in RET gene
Autosomal dominant
Protein function involved in Hirschsprung disease and RET gene
tyrosine kinase receptor
Proto-oncogene
genes that code for proteins that help regulate cell growth
what cell is RET gene expressed in
neural crest cells
Hirschsprung is what kind of mutation
Loss-of-function
Loss-of-function mutation
reduced or abolished protein function
What syndrome is associated with gain-of-function mutation
MEN (multiple endocrine neoplasia) syndrome
Gain-of-function
type of mutation in which altered gene product has new function or new pattern of expression
Function of RET gene
gives instructions to proteins that are involved in signaling within cells
RET and Hirschsprung disease association
result in nonfunctional RET protein
Result of no RET protein signaling
enteric nerves do not develop
Hemochromatosis
liver disorder
Etiology of hemochromatosis
Decrease in HFE function
Function of AAT
protect the cell from elastase overactivation`
2 diseases/syndromes associated with hemochromatosis
Wilson disease and Menkes syndrome
Secondary hemochromatosis
not genetically related- but due to build-up of iron from anemia, liver disease, or alcoholism
Iron overload through too much absorbed
iron is excess of transferrin capacity
Where does iron excess deposit in the body
liver, heart, and endocrine organs
What can iron excess in body lead to
tissue damage and fibrosis of liver, heart, and endocrine organs
Iron overload through too many erythrocytes destroyed
accumulates in macrophages first then tissue parenchyma
Most common gene associated to iron absorption regulation
HFE
Mode of inheritance for HFE gene
autosomal recessive
Factors that decrease iron absorption
regular blood transfusions, high iron diet, iron loading vitamins
Factors that increase iron absorption
celiac disease, pica, GI bleeding
HFE function
regulate circulating iron uptake by regulating transferrin receptor (TFR1/2) and transferrin
Hepcidin
regulator of entry of iron into circulation
Transferrin
iron-binding blood plasma glycoprotein that controls level of free iron
Ferroportin
transmembrane protein that transports iron from inside cell to outside cell
What inhibits ferroportin
hepcidin
T/F hemochromatosis is common in young infants
F- late onset, 40-50 males and later onset in females
S/S of hemochromatosis
increased pigmentation, fatigue, hepatospenomegaly
Endocrine organs affected by hemochromatosis
diabetes (pancreas), hypopituitarism (pit), hypogonadism (gonad), hypoparathyroidism (thyroid)
Skin color of person with hemochromatosis
bronze skin
ONLY sign or symptom specific to hemochromatosis
“The Iron Fist”
Treatment for hemochromatosis
therapeutic phlebotomy to remove iron in blood
Hereditary hemochromatosis gene
C282Y - cys to tyr mutation
Incidence of hemochromatosis
Northern European ancestry
Two genes involved in copper homeostasis
ATP7A and ATP78
Ceruloplasmin
major copper-carrying protein in the blood and iron metabolism
Regulation of iron absorption by ceruloplasmin
ceruloplasmin promotes iron loading onto transferring with only binds Fe2+ –> reduced Cu2+ transports Fe2+ to increase Fe2+ absorption
Gene associated with Menkes Syndrome
ATP7A
If ATP7A is mutated
Menkes Syndrome- uptake of copper impaired and copper deficiency occurs
Clinical presentation of Menkes
infant healthy until 2-3 months, loss of developmental milestones, hypotonia, and failure to thrive
MAIN sign of Menkes
kinky hair, short, sparse, lightly pigmented
Vessels of Menkes patient
very tortuous blood vessels
Gene associated with Wilson disease
ATP7B
ATP7B mutations for Wilsons disease
prevent release of Cu2+ from hepatocytes causing decreased ceruloplasmin levels and Fe2+ and Fe3+ affected
S/S of Wilsons Disease
progressive lenticular degeneration, softening of lenticular nucleus, liver cirrhosis
Clinical presentation of Wilsons Disease
movement disorders, rigid dystonia, Kayser-Fleischer ring
Kayser-Fleischer ring
copper deposition in Descemet’s membrane of cornea
Copper levels in liver of Menkes syndrome
decreased
Copper levels in liver of Wilsons
increased
Serum copper in Menkes and Wilsons
decreased
Treatment for Menkes
daily copper/histidine injections
Treatment for Wilsons
copper chelation
