W1_03 Mendelian Disorders Flashcards
what are 3 mechanisms by which mutations lead to disease?
gain of function;
loss of function;
disruption of a multiprotein complex
what’s a missense mutation?
single base change, resulting in an amino acid change
what’s a nonsense mutation?
single base change, resulting in a stop codon in the AA sequence
what’s a frameshift mutation?
an insertion or deletion in the DNA that shifts the codons and changes all the amino acids downstream
if the father transmits a genetic disease to his son, which type of single gene disease is ruled out?
it can’t be x-linked
why does disease occur in AD conditions despite the presence of the normal gene product?
haploinsufficiency;
dominant-negative effect;
function-enhancing mutation;
random/somatic loss of other copy may occur
define penetrance
an all-or-nothing phenomenon, describing the fraction of people with the mutation that show symptoms
define expressivity
describes the range and severity of symptoms an affected individual may have
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?
autosomal dominant
cystic fibrosis is caused by which gene?
mutation in the CF transmembrane conductance regulator gene (CFTR)
what kind of single gene mutation is CF?
autosomal recessive
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?
autosomal recessive
what are major phenotypic features of DMD?
age of onset - childhood; muscle weakness; calf hypertrophy; moderate intellectual compromise; elevated serum creatine kinase levels
the DMD gene codes for which protein?
dystrophin, which maintains muscle integrity and assembly of the synaptic junction
note: males with DMD don’t typically reproduce
ok
note: about 2/3 of DMD patients are the result of carrier mothers
recall, it’s an x-linked disease
define germline mosaicism
where a fraction of germ cells can have mutations. e.g. germline mosaicism in DMD
which x-linked condition was common among the descendants of britain’s queen victoria, who was a carrier?
hemophilia a
what is hemophilia a?
it’s a factor VIII activity deficiency that has variable expressivity. treated with IV replacement of factor VIII
what’s x-inactivation?
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
what’s skewed x-inactivation
when the x that has the mutation is active in most cells and the female gets clinical symptoms of the disease
how can x-linked diseases occur in females?
skewed x-inactivation;
x-linked dominant
rett syndrome, chronic granulomatous disease, fabry disease, x-linked hypophosphatemic rickets are which kind of single gene mutation?
x-linked
heart disease, autism, obesity, cancer, congenital anomalies (cleft lip, neural tube, CHD, etc) are examples of what?
multifactorial genetic disease
note: multifactorial diseases are less heritable than single gene disorders
ok
name 2 autosomal dominant disorders
FAP;
achondroplasia
name 2 autosomal recessive disorders
cystic fibrosis;
sickle cell anemia
name 2 x-linked disorders
hemophilia A;
duchenne muscular dystrophy
