W1_03 Mendelian Disorders

Question 1

what are 3 mechanisms by which mutations lead to disease?

Answer 1

gain of function;
loss of function;
disruption of a multiprotein complex

Question 2

what’s a missense mutation?

Answer 2

single base change, resulting in an amino acid change

Question 3

what’s a nonsense mutation?

Answer 3

single base change, resulting in a stop codon in the AA sequence

Question 4

what’s a frameshift mutation?

Answer 4

an insertion or deletion in the DNA that shifts the codons and changes all the amino acids downstream

Question 5

if the father transmits a genetic disease to his son, which type of single gene disease is ruled out?

Answer 5

it can’t be x-linked

Question 6

why does disease occur in AD conditions despite the presence of the normal gene product?

Answer 6

haploinsufficiency;
dominant-negative effect;
function-enhancing mutation;
random/somatic loss of other copy may occur

Question 7

define penetrance

Answer 7

an all-or-nothing phenomenon, describing the fraction of people with the mutation that show symptoms

Question 8

define expressivity

Answer 8

describes the range and severity of symptoms an affected individual may have

Question 9

polycystic kidney disease, achondroplasia, marfan’s syndrome, FAP, hereditary breast/ovarian cancer, myotonic dystrophy, and huntington’s are examples of which kind of single gene mutation?

Answer 9

autosomal dominant

Question 10

cystic fibrosis is caused by which gene?

Answer 10

mutation in the CF transmembrane conductance regulator gene (CFTR)

Question 11

what kind of single gene mutation is CF?

Answer 11

autosomal recessive

Question 12

sickle cell anemia, non-syndromic deafness (connexin 26), inborn metabolism errors (PKU, MPS, gaucher’s, tay-sachs), and thalassemia are which kind of single gene mutation?

Answer 12

autosomal recessive

Question 13

what are major phenotypic features of DMD?

Answer 13

age of onset - childhood;
muscle weakness;
calf hypertrophy;
moderate intellectual compromise;
elevated serum creatine kinase levels

Question 14

the DMD gene codes for which protein?

Answer 14

dystrophin, which maintains muscle integrity and assembly of the synaptic junction

Question 15

note: males with DMD don’t typically reproduce

Answer 15

ok

Question 16

note: about 2/3 of DMD patients are the result of carrier mothers

Answer 16

recall, it’s an x-linked disease

Question 17

define germline mosaicism

Answer 17

where a fraction of germ cells can have mutations. e.g. germline mosaicism in DMD

Question 18

which x-linked condition was common among the descendants of britain’s queen victoria, who was a carrier?

Answer 18

hemophilia a

Question 19

what is hemophilia a?

Answer 19

it’s a factor VIII activity deficiency that has variable expressivity. treated with IV replacement of factor VIII

Question 20

what’s x-inactivation?

Answer 20

in females, when the embryo is about 100 cells, each of those cells will inactivate one of the x chromosomes for itself and all future progenitors of that cell. thus, a female will have 50% paternal x and 50% maternal x in her body

Question 21

what’s skewed x-inactivation

Answer 21

when the x that has the mutation is active in most cells and the female gets clinical symptoms of the disease

Question 22

how can x-linked diseases occur in females?

Answer 22

skewed x-inactivation;

x-linked dominant

Question 23

rett syndrome, chronic granulomatous disease, fabry disease, x-linked hypophosphatemic rickets are which kind of single gene mutation?

Answer 23

x-linked

Question 24

heart disease, autism, obesity, cancer, congenital anomalies (cleft lip, neural tube, CHD, etc) are examples of what?

Answer 24

multifactorial genetic disease

Question 25

note: multifactorial diseases are less heritable than single gene disorders

Answer 25

ok

Question 26

name 2 autosomal dominant disorders

Answer 26

FAP;

achondroplasia

Question 27

name 2 autosomal recessive disorders

Answer 27

cystic fibrosis;

sickle cell anemia

Question 28

name 2 x-linked disorders

Answer 28

hemophilia A;

duchenne muscular dystrophy