ROBBINS Flashcards
1
Q
two most common forms of DNA variations
A
SNPs (single nucleotide polymorphisms) and CNVs (copy number variations)
2
Q
define : miRNAs
A
microRNA - they do not encode proteins but INHBIT gene expression - involved in post-transcriptional modification
3
Q
3 categories of human genetic disorders
A
- single mutations that produce large effects - AKA mendelian disorder ( high penetrance )
- chromosomal disorders
- complex multigenic disorders ( low penetrance )
4
Q
define : polymorphisms
A
variations in genes that are common within a population
5
Q
define : mutation
A
permanent change in DNA
6
Q
define : penetrance
A
proportion of individuals with a certain gene mutation that exhibit the clinical symptoms
7
Q
define : point mutations
A
when one nucleotide base is SUBSTITUTED for another base
8
Q
define : frameshift mutations
A
INSERTIONS/DELETIONS that can alteration in the reading frame of DNA strand
9
Q
point mutation that alters the sequence of the encoded protein is AKA
A
missense mutation
can be conservative or non-conservative
10
Q
point mutation that changes the nucleotide to a stop codon
A
nonsense mutation
11
Q
if the insertion/deletion mutation is a multiple of 3 then?
A
it CAN’T be a frameshift mutation
-the protein just contains either one more/one less amino acid
12
Q
*fragile X syndrome
A
type of trinucleotide repeat mutation
CGG on familial mental retardation 1 (FMR1)
13
Q
which receptor does HIV use to enter cells
A
CCR5
14
Q
define : codominance
examples?
A
when both of the alleles of a gene contribute to the phenotype
( HLA and blood group )
15
Q
define : pleiotropic
A
when a single mutant gene leads to many end effects
16
Q
define : genetic heterogeneity
A
when mutations at several different loci produce the same effect
17
Q
when an individual inherits the mutant gene but is phenotypically normal
A
incomplete penetrance
18
Q
when a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals
A
variable expressivity
19
Q
do autosomal dominant mutations affect enzyme proteins
A
NO, b/c 50% loss of enzyme activity can be compensate for
20
Q
what are the two major classes of nonenzyme proteins that are affected by AD disorders
A
- enzymes involved in complex metabolic pathways that are subject to feedback inhibition ( ie. LDL )
- key structural proteins ( spectrin )
21
Q
are LOF or GOF mutations more common
A
LOF
22
Q
AD disorders - nervous system
A
Huntington disease - neurofibromatosis - myotonic dystrophy - tuberous sclerosis
23
Q
AD disorders - urinary
A
polycystic kidney disease
24
Q
AD disorders - GI
A
familial polyposis coli
25
AD disorders - hematopoietic
hereditary spherocytosis - von willebrand disease
26
AD disorders - skeletal
marfan syndrome - ehlers danlos - osteogenesis imperfect - achondroplasia
27
* characteristics of AR disorders
1. parents are usually unaffected, but siblings show the disease
2. siblings have 1/4 chance of having the trait
28
* characteristics of X-linked disorders
1. affected male parent cant pass onto sons, but all daughters are carriers
2. sons of heterozygous women have 50% of getting the mutant gene
29
most metabolic disorders are?
AR
30
X linked - MSK
duchenne muscular dystorphy
31
X linked - blood
hemophilia A and B
chronic granulomatous disease
G6PD
32
X linked - immune
agammaglobulinemia
| wiskott-aldrich syndrome
33
X linked - metabolic
DI
| lesch-nyhan syndrome
34
X linked - nervous
fragile X syndrome
35
deficient enzyme in GALACTOSEMIA
galactose-1-phosphate uridyltransferase
36
what makes melanin?
tyrosine + the enzyme TYROSINASE - results in albinism
37
the defect in familial hypercholesterolemia
reduced function of LDL receptors leads to defective transport of LDL into cells, which causes increased cholesterol production
38
which drugs can cause severe hemolytic anemia is G6PD patients
primaquine
| sulfonamides
39
mode of inheritance of MARFAN syndrome
AD
40
gene deletion product in MARFANs
extracellular glycoprotein - fibrillin-1
41
what is the function of fibrillin
fibrillin is a major component of microfibrils which are needed to make elastic fibers
42
what sites are primarily affected in MARANs
elastic tissue - lens of eye, aorta, skeleton
43
which actual genes are affected in MARFANs
FBN1 15q21.1
| ( FBN2 causes congenital contractural arachnodactyly )
44
what other factor contributes to MARFANs
excessive TGF-Beta production
45
what ocular feature is seen in MARFAN
ectopia lentis - outward and upward dislocation of the lens
46
*two MC cardiovascular lesions seen in MARFANs
MVP and dilation of ascending aorta (MCCOD)
47
*clinical features in MARFANs
mitral regurgitation
tall, with long extremities
double jointed
ectopia lentis
48
*clinical features if EDS
skin is hyperextensible - joints are hypermobile - skin is easily damaged -
49
MC AR EDS
kyphoscoliosis
50
defect in kyphoscoliosis EDS
the enzyme LYSYL HYDROXYLASE - w/o it cant cross link collagen fibers
51
defect in vascular EDS?
| clinical findings?
type 3 collagen
| thin skin, arterial and uterine rupture (GI!), bruising, small joint hyper-extensibility
52
EDS type with type 1 collagen defect
arthrochalasia
| defect is procollagen to collagen
53
mutation in procollagen-N-peptidase gene causes
EDS - dermatosparaxsis type
| AR inheritance
54
EDS classical type defect
collagen type 5
55
which gene is mutated in FAMILIAL HYPERCHOLESTEROLEMIA
gene for LDL receptor
56
how is LDL made
1. lives makes VLDL
2. LPL on capillaries cleaves VLDL to IDL
3. IDL can either be recycled back to VLDL in the liver or made into cholesterol rich LDL
57
what is the immediate and major source of plasma LDL
IDL
58
which apoproteins are on
1. VLDL
2. IDL
3. LDL
1. B-100, ApoE, ApoC
2. B-100, ApoE
3. B-100
59
what is needed for cholesterol to exit the lysosomes inside the cell?
NPC 1 and NPC2
| niemann-pick disease- type C
60
* which processes are affected by intracellular cholesterol
1. cholesterol suppresses 3-hydroxy-3methylglutaryl coenzyme A (HMG CoA) reductase
2. cholesterol activates acyl-coenzyme A:cholesterol acyltransferase - which promotes storage of excess cholesterol as esters
3. suppresses LDL receptor production to prevent excess cholesterol in cell
61
how do statins works
inhibit HMG-CoA thus preventing cholesterol synthesis in the cell and increasing the number of LDL receptors as a way to increase the intracellular cholesterol level
62
what are the class mutation is familial hypercholesterolemia ?
```
class 1 - no synthesis in ER
class 2 - cant get to Golgi
class 3 - defective receptor
class 4 - normal receptor but cant be internalized
class 5 - internalized but cant be released by endosome so it is degraded
```
63
lysosomes contain?
| what are there properties?
hydrolytic enzymes. work in acidic environment and they are SECRETORY enzymes that affect INTRACELLULAR organelles
64
what special modification occur in the Golgi involving lysosomes?
a *terminal mannose-6-phosphate group* is added. this segregates these specific enzymes from the other ones in the Golgi.
65
autophagy vs heterophagy
autophagy is lysosomal breakdown of products that originate from INSIDE the cell and while heterophagy originates from OUTSIDE the cell
66
the 5 major classes of LYSOSOMAL STORAGE DISORDERs
1. glycogenosis
2. sphingolipidoses
3. sulfatidoses
4. mucopolysaccharidoses
5. mucolipidoses
67
type 2 - glycogenosis
| enzyme defect and accumulating metabolite
POMPE disease
| alpha 1,4 - glucosidase (lysosomal glucosidase) - glycogen
68
sphingolipidoses types
Gm1 gangliosidosis - type 1 infantile and type 2 juvenile
| Gm2 gangliosidosis - TAY-SACHS*, Sandhoff disease
69
enzyme defect and accumulating metabolite in TAY-SACHS disease
hexosaminidase A - Gm2 ganglioside
70
enzyme defect and accumulating metabolite in Sandhoff-disease
hexosaminidase B - Gm2 ganglioside, globoside
71
enzyme defect and accumulating metabolite in Gm1 gangliosidosis
Gm1 ganglioside B-galactosidase - Gm1 ganglioside
72
enzyme defect and accumulating metabolite in METACHROMATIC LEUKODYSTROPHY
type of sulfatidoses -
| arylsulfatase A - sulfatide
73
enzyme defect and accumulating metabolite in MULTIPLE SULFATASE DEFICIENCY
arulsulfatase A,B,C and different sulfatase - sulfatide, steroid suflate, heparin sulfate
74
enzyme defect and accumulating metabolite in KRABBE disease
galactosylceramidase - galactocerebroside
75
enzyme defect and accumulating metabolite in FABRY disease
alpha-galactosidase A - ceramide trihexoside
76
enzyme defect and accumulating metabolite in GAUCHER disease
glucocerebrosidase - glucocerebroside
77
enzyme defect and accumulating metabolite in NIEMANN PICK disease A and B
sphingomyelinase - sphingomyelin
78
types of MPSs
1. MPS 1 (hurler)
| 2. MPS 2 (hunter)
79
enzyme defect and accumulating metabolite in HURLER
alpha-L-iduronidase -- dermatan sulfate, heparin sulfate
80
enzyme defect and accumulating metabolite in HUNTER
L-iduronosulfate sulfatase -- dermatan sulfate, heparin sulfate
81
clinical presentation of HUNTER
male (X-linked) with aggressive behavior and good vision (NO corneal clouding)
82
clinical presentation of FABRY
peripheral neuropathy and CV manifestation
| also X-linked
83
morphology of TAY SACHSs
neurons are ballooned with vacuoles because of Gm2 ganglioside deposition - stains for oil red O and sudan black B are positive - CHERRY RED SPOT - EM shows lysosomes with WHORLED configuration
84
clinical presentation of TAY SACHs
signs being at 6 months - progressive dementia, motor incoordination, muscular flaccidity, blindness
CHERRY RED SPOT +
HEPATOSPLENOMEGALY -
85
NIEMANN PICK disease type A
severe infantile form - complete loss of sphingomyelinase - death within first 3 years of life
86
NIEMANN PICK disease type B
organomegaly WO CNS manifestations - survive into adulthood
87
clinical manifestation in NIEMANN PICK disease
CHERRY RED SPOT +
| hepatosplenomegaly +
88
morphology of NIEMANN PICK disease
sphingomyelin and fat accumulates in cells ( neurons and hepatocytes ) -- lysosomes contain concentric lamellated myelin figures called ZEBRA BODIES - shrunken gyri and widened sulci
89
clinical presentation of NIEMANN PICK type C
presents in childhood with ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression
90
the MC lysosomal storage disorder
GAUCHER disease
91
GAUCHER disease type 1
chronic non-neuronopathic form
- limited to mononuclear phagocytes
- NO brain involvement
- spleen and skeleton highly involved
92
GAUCHER disease type 2
acute neuronopathic form - infantile acute cerebral pattern
- NO predilection for jews
- no glucocerebrosidase activity in tissues
93
* describe GAUCHER cells
distended phagocytic cells that have cytoplasm that looks like CRUMBED PAPER
94
WRIGHT stain used for
peripheral blood smear to differentiate between blood cells
95
general clinical features of the MPSs
* coarse facial features, clouding of the cornea, joint stiffness, mental retardation*
- hepatosplenomegaly, skeletal deformities, valvular lesions, subendothelial arterial deposits
96
basic formation of glucose to glycogen
1. glucose to glucose-6-phosphate via hexokinase (glucokinase)
2. glucose-6-phosphate to glucose-1-phosphate via phosphoglucomutase
3. glucose-1-phosphate to uridine disphospoglucose
97
basic breakdown of glycogen
glycogen to glucose-1-phosphate until only 4 glucose residues are left -- known as limit dextrin , which is further broken down by debranching enzyme
98
glycogen degraded by which enzyme in lysosomes
acid maltase ( alpha-glucosidase )
99
define : isochromosome
when one arm of the chromosome is deleted and the remaining one is duplicated - either two long arms or two short arms
100
MCC of trisomy
meiotic nondisjunction
101
*clinical features of trisomy 21
flat facial profile, oblique palpebral fissures, epicanthic folds, congenital heart defects, predisposition to leukemia+neurodegenerative disease+serious infections, gap btw first and 2nd toe,
102
trisomy 18
Edwards syndrome
| - micrognathia, overlapping fingers, low+misshapen ears, renal malformations, rocker bottom feet
103
trisomy 13
Patau syndrome
| -cleft lip and palate, microphthalmia, rocker bottom feet, umbilical hernia, cardiac defects
104
22q11 deletions cause
digeorge syndrome
| + velocardiofacial syndrome
105
androgen receptor gene
on X chromosome (Xq12)
| -contains CAG repeats-with shorter repeats, the effects of testosterone is greater.
106
gene important in stature
SHOX - deletion leads to short stature (TURNER syndrome)
| -excess copy leads to tall stature
107
*clinical features of TURNER syndrome
short stature, cystic hygroma in neck leads to webbing, hypothyroidism due to autoantibodies, peripheral edema, CV malformations PREDUCTAL COARCTATION OF AORTA + BICUSPID VALVE, no 2ndary sex characteristics, AMENORRHEA, broad chest
108
MCC of primary amenorrhea
TURNER syndrome
109
define : true hermaphrodite
implies the presence of both ovarian and testicular tissue
110
define : pseudohermaphrodite
disagreement between gonadal sex and phenotypic
111
MC form of male pseudohermaphroditism
androgen insensitivity syndrome due to androgen receptor mutation
112
trinucleotide repeats in oogensis
fragile x syndrome
113
trinucleotide repeats in spermatogenesis
HD
114
trinucleotide repeats in exons vs intron
exons-HD
| introns- myotonic dystrophy and fragile X
115
repeat in FRAGILE X
CGG
116
repeat in FRIEDREICH ATAXIA
GAA
117
repeat in MYOTONIC DYSTROPHY
CTG
118
repeat in HD
CAG
119
repeat in spinocerebellar ataxia
CAG
120
2nd MCC of mental retardation
fragile X syndrome
121
physical phenotype in FRAGILE X syndrome
long face with large mandible, large everted ears, large testicles
-hyperextensible joints, MVP mimics CT disorder
122
most distinctive feature of FRAGILE X
macro-orchidism
123
premutations get converted to mutation where
oogenesis only
124
mtDNA comes from
MOM only
125
human mtDNA codes for
37 total genes-
22 for tRNA-
2 for rRNA-
13 for respiratory chain enzymes
126
define : heteroplasmy
when you have both wild type and mutant mtDNA
127
prototypical mtDNA disorder
leber hereditary optic neuropathy
| progressive b/l loss of central vision
128
define : maternal imprinting
transcriptional silencing of maternal allele for a gene
129
where does imprinting occur
in the sperm or ovum, before fertilization
130
*clinical features of PRADER-WILLI
short stature, hypotonia, hyperphagia, obesity, small hands and feet, hypogonadism
131
deletion in PRADER-WILLI
paternal chromosome 15q12
| the maternal allele is imprinted and therefore inactive
132
deletion in ANGELMANN syndrome
maternal chromosome 15q12
| the paternal allele is imprinted and therefore inactive
133
*clinical features of ANGELMANN
mental retardation, ataxic gait, seizures, inappropriate laughter
134
define : uniparental disomy
inheritance of both chromosomes of a pair from one parent
135
define : gonadal mosaicism
mutation during embryogenesis of only gonads and not somatic cells
i.e phenotypical normal parent who can transmit disease causing mutation through gametes
136
mutation in CML
BCR-ABL
