L9 - molecular mechnaisms of mendelian disorders

Question 1

eg of a quantitative lof disease

loss of a pr product

Answer 1

thalessemia

Question 2

describe the genetic of thalessemia

Answer 2

auto rec
both a and b typess
point mut or del
in greek cypriot high incidence in gene inv in rna splicing

Question 3

describe the ptype result fom the lof mut in thalessemia

Answer 3

decr rate of synth/no synth of the globin chains that make up hb
mut in alpha globin chain - alpha thalessemia

Question 4

eg of a qualitative lof disease (pr present but loss of qual/fucntion)

Answer 4

sickle cell anaemia

Question 5

describe the genetic of sickle cell

Answer 5

auo rec

mut a single chnage in beta globin gene at codon 6 gag to gtg

Question 6

describe the ptype of sickle cell

Answer 6

the mut results in the beta globin chains sticking together
this distorts rbc into a sickle cell shape and reduction in flexibility
can lead to microvascular thrombosis

Question 7

eg of a disease cause by mut in regulatory

Answer 7

haemophilia beta

Question 8

describe the genetic of haemophilia beta

Answer 8

x lined rec
mut in promoter factor IX gene
the muts are in the binding sites for tf inc LFIA and HNF4 - haemophilia beta leyden
other muts in anrogen response element - haemophilia beta brandenburg

Question 9

what eg of diseases caused by large deletions

Answer 9

duchene muscular dystrophy

becker muscular dystrophy

Question 10

what gene effected in duchene muscular dystrophy (dmd)

becker muscular dystrophy (bmd)

Answer 10

DMD gene
big over 2mbp
encodes dystorphin gene
a strucutral pr anchors contractile machinery to sacrolemma - makes a fixed but flexilbe strcutre for muscle contraction

Question 11

what are the similarities in dmd and bmd

Answer 11

both x link rec
caused by del in DMD
both have ptype with progressive muscle weakness (same clinical)

Question 12

differences in dmd and bmd occurence

Answer 12

dmd more common 1:3000
bmd 1:20000
dmd earlier onset ok up to 10 then wheelchair and dead by 30
bmd later and norm long life span

Question 13

sim and differences in dmd and bmd genetics

Answer 13

in both 65% del of DMD
DMD gene 99% of it intron
no corr with size of del and severity of ptype
thought -
dmd- del that cause frameshifft - no dystorphin pr
bmd - del leave reading frame intact - smaller but functional pr
=

Question 14

give eg of gain of fucntion disease

Answer 14

T cell acute lymphoblastic leukaemia

noonan syndrome

Question 15

what the genetic of T cell acute lymphoblastic leukaemia

Answer 15

notch 1 mut in over half of patients

activated mut mut norm in heterodimerisation domain or c-terminal pest domain

Question 16

what the genetic of noonan syndrome

Answer 16

muts inc PTPN11 codes oncogene shp2 phosphotase
sph2 regulate Ras/MAPK pathway inv in cell prolif/migr and apop
=imp in dev of heart/blood

Question 17

what the clinical features of noonan syndrome

Answer 17

facial dysmorphology
short stature
heart defect

Question 18

what are diseases of dominant negative effect

Answer 18

the mutated product interferes with the normal product prod in hetero
special case of lof

Question 19

what genes often inv in syndromes of dominant negative effect

Answer 19

collagen genes

mut pr norm has dom negative effect on tiple helix assembly of the collagen fibre

Question 20

eg of diseases of dominant negative effect

Answer 20

osteogensis imperfect type III
stickler syndrome
brain vessel disease

Question 21

descibe osteogensis imperfect type III -

Answer 21

mut in cola1 or cola2

results in severe bone fragility/malform/ short stature

Question 22

descirbe stickler syndrome

Answer 22

hereditry arthro-ophalamopathy
mut in col2a1 
inc splicing errors and smaller del
distinctive facial abn / ocular problems 
retinal detachment and cataracts

Question 23

describe brain vessel disease

Answer 23

mut in col4a1 disease
hemorrhagic stroke
ischeamic stroke
retinal arteriolar tortuosity

Question 24

give eg of disease in which nature of the mutation effect the syndrome

Answer 24

haemoglobinopathy

notchopathy

Question 25

desrcibe symptoms of haemoglobinopathy

Answer 25

from anaemia to symptomless
the most common mut is a gllutamic acid to valine - sickle cell
other aa sub decr the hb synth /instability of hb mol
some have high oxygen affinity

Question 26

describe the genetics and ptype of notchopathy

Answer 26

mut in HD PEST domain in notch - GOF

mut in other region of notch - aortc valve disease

Question 27

how can geentic background effect disease

Answer 27

polymorphs of the same gene may influence on disease ptype

modifying genes

Question 28

give an eg of a polymorphs of the same gene influencing disease ptype

Answer 28

polymorph H558R has mut specific effect on SCNC5A related suck sinus syndrome

Question 29

give eg of modifying genes effecting disease ptype

Answer 29

alpha thalessemia and beta thallesemia inhibit together
in alpha thaa excess alpha chain damages red cell precursors
coinherit a thal ameliorates b thal ptype