Genetics Flashcards
1
Q
Rarest form of CAH
Two genes
Mutations
-Type I (placenta, skin, mammary gland)
-Type II (adrenal gland and gonads)
-46,XY DSD – male is hypomasculinized
-46,XX DSD – clitoromegaly
-Adrenal hyperplasia
A
3B-hydroxysteroid dehydrogenase deficiency
2
Q
MC cause of CAH
Autosomal recessive
Impaired synthesis of cortisol from cholesterol in adrenal cortex
Virilization in all individuals (androgen excess)
Salt-wasting (due to lack of aldosterone)
Deficiency of cortisol
A
21-hydroxylase deficiency
3
Q
Males:
- Premature body hair loss
- Enlarged penis with small testes
- Decreased sperm count
- Short stature
Females:
- Premature adrenarche/menarche
- Menstrual abnormalities
- Balding
- Excess hair growth
- PCOS
M & F:
- Premature growth of body hair
- Body odor
- Early rapid growth
- Acne
A
Non-classical 21-hydroxylase deficiency
4
Q
Difference between “classic” and “mild/non-classical” forms of CAH:
A
“Classical” CAH:
- Virilizing form
- Salt-wasting (newborns at risk for life-threatening crises)
“Mild/non-classical” CAH:
- Later onset
- MC than classic – may have normal height, but short when compared to parents
- Moderate enzyme deficiency – limited glucocorticoid response to stress
5
Q
Prenatal virilization in females
Postnatal virilization in males and females
Salt-wasting (in 75%)
Cortisol deficiency (in 100%)
A
Classic 21-hydroxylase deficiency
6
Q
Prenatal virilization absent
Postnatal virilization variable
Salt-wasting absent
Cortisol deficiency rare
A
Non-classical 21-hydroxylase deficiency
7
Q
Dx confirmation for CAH involves the molecular genetic testing of:
A
CYP21A2
8
Q
Dx confirmation for CAH may also involve biochemical findings such as elevated serum:
A
17-OHP
17-OHP unable to be converted to 11-deoxycortisol
( >20,000 ng/dL = classic)
(2,000 – 15,000 ng/dL = non-classical)
9
Q
Tx for classic 21-hydroxylase deficiency CAH:
A
Glucocorticoid replacement therapy
- Increased during periods of stress
- Salt-wasting pts – Rx 9a-fludrohydrocortisone and NaCl
10
Q
An infant with a sibling affected with CAH does not have elevated 17-OHP. What is the probability that this infant is a carrier?
A
66%
11
Q
Excess adrenal androgens in utero:
- Before 12 weeks:
- After 12 weeks:
A
Excess adrenal androgens in utero:
- Before 12 weeks: Labioscrotal fusion, clitoral enlargement
- After 12 weeks: Clitoral enlargement
12
Q
Excess adrenal androgens after birth:
- Precocious puberty
- Untreated males:
- Untreated females:
A
Excess adrenal androgens after birth:
- Precocious puberty
- Untreated males: progressive penile enlargement and small testes
- Untreated females: clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, reduced fertility
13
Q
Second MC cause of CAH Most mutations abolish activity Females: -Ambiguous or masculinized external genitalia -Virilization during childhood Males: -Normal external genitalia -Virilization early DOC and 11B-deoxycortisol are increased (NO salt-wasting) HTN*** (distinguishes from 21-OHD)
A
11B-hydroxylase deficiency
14
Q
What are the two genes associated with 11B-hydroxylase?
A
CYP11B1
CYP11B2
15
Q
In the zona glomerulosa, 11B-hydroxylase has 3 enzyme activities:
- 11B-hydroxylase
- 18-hydroxylase
- 18-oxidase
All activities are coded for by which gene?
A
CYP11B2
16
Q
18-hydroxylase and 18-oxidase are involved in the conversion of corticosterone to:
A
Aldosterone
17
Q
HMG octamer mutations ->
No binding to DNA ->
No male differentiation ->
46,XY female
What gene is mutated?
A
SRY
18
Q
The Pseudoautosomal Region (PAR) pairs and recombines with X-chromosome. SRY is near but not in PAR. Therefore, Recombination may translocate this gene to the X-chromosome, resulting in 46,XX but phenotypically demonstrating:
A
46,XX with male phenotype
19
Q
What is required for SRY expression and gonads/adrenal development (sex determination, sex differentiation, steroidogenesis, lipid metabolism)?
A
Steroidogenic Factor 1 (SF1)
20
Q
Congenital adrenal hypOplasia and hypogonadotropic hypogonadism is due to a mutation or deletion in which gene?
A
DAX1
(normally down-regulated in developing testes but not in ovary)
-Duplication in males -> 46,XY females
-Duplication in females -> no effect
21
Q
Dosage sensitive sex reversal-Adrenal sensitive sex reversal on the X Chr (DAX1 gene) is important in development of the ovary and down regulation in developing testes. What happens if it is duplicated in males? MoA?
A
Duplicated DAX1 -> 46-XY female
SRY may inhibit DAX1, but in duplicated state, there may be insufficient SRY to repress DAX1 expression
22
Q
- Result of SOX9 mutations -> Mullerian ducts do not degenerate (ovary development occurs)
- Associated with sex reversal due to gonadal dysgenesis in 46,XY
- Bowing of long bones
- Shortened long bones
- Skeletal dysplasia
A
Campomelic dysplasia
“bent limbs”
23
Q
WT1 and SF1 expression are required for which gene to be expressed?
A
SRY
24
Q
SRY expression in Sertoli cells up-regulates which gene?
A
SOX9
25
SRY mutations
SOX9 mutations
DAX1 mutations
All result in:
Sex reversal
26
- Abnormality of anterior urethral development in which the urethral opening is ectopically located on the ventral side of the penis proximal to the tip of the glans penis
- Defect occurs between weeks 8-20
Hypospadias
27
- Both ovarian and testicular tissue in one or both gonads
- Internal and external differentiation is variable
- Ovotestis is the MC gonad found
Ovotesticular DSD
28
- Aromatase (CYP450-aromatase) deficiency
- Expressed in ovary and testis
- Tissue-specific promoters
- Elevated testosterone and androstenedione
- Masculinization of female genitalia
- Pubertal failure
Female 46,XX DSD
29
- Abnormalities of gonad development
- Cholesterol synthesis defects
- Testosterone synthesis defects
- Testosterone metabolism defects
- Androgen action defects
- Persistence of Mullerian ducts syndrome
- Congenital non-genetic 46,XY DSD
Male 46,XY DSD
| more complicated
30
* Prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation, and multiple major and minor malformations.
* Malformations include distinctive facial features, cleft palate, cardiac defects, **underdeveloped external genitalia in males**, postaxial polydactyly, and 2-3 syndactyly of the toes.
* Clinical spectrum is wide and individuals have been described with normal development and only minor malformations.
Abnormal cholesterol synthesis in 46,XY DSD
| "Smith-Lemli-Opitz syndrome"
31
• Impaired Leydig cell differentiation
• Defects in adrenal and testicular
steroidogenesis
• P450scc deficiency
• 3β hydroxysteroid dehydrogenase deficiency
• 17α hydroxylase deficiency
• 17β hydroxysteroid dehydrogenase deficiency (MC)
Testosterone synthesis defects in 46,XY DSD
32
• 46,XY with female external genitalia
• Testes and Wolffian derivatives present
• At puberty – absence of male differentiation – Deepening voice
– Clitoral enlargement – Hirsutism
– Male muscularity
– Breast development
17B-hydroxysteroid dehydrogenase deficiency
33
- Female genitalia
- Partial virilization at puberty
- Elevated testosterone:DHT ratio
5a-reductase deficiency
(testosterone metabolism defects)
(46,XY DSD)
34
• Deficient conversion of testosterone to DHT
– Deficient DHT to bind to androgen receptor
• Two isozymes
– Type 2: Expressed before and after birth
» Prostate, Wolffian derivatives, scrotum, liver
– Type 1: Expressed in non-genital tissues
• Mutation in female - genitalia normal; menarche delayed
• Mutation in male - testes extra-abdominal; usually inguinal – Hypospadic microphallus
– Blind vaginal pouch
5a-reductase deficiency
(testosterone metabolism defects)
(46,XY DSD)
35
• Steroid hormone receptor family
• Mediates growth and differentiation in AR responsive tissues
Lipid soluble ligand enters cell ->
Binds to receptor with HSP sequence and displaces HSP ->
Transported into nucleus ->
Binds to hormone response element
What receptor is described?
Androgen receptor
| 46,XY DSD
36
• Androgeninsensitivitysyndrome
– Complete and partial forms
– Mutations in the androgen receptor (Transcription factor)
Androgen insensitivity syndrome
| 46,XY DSD
37
* Defect in AMH synthesis
| * Defect in AMH receptor
Persistence of Mullerian duct syndrome
| 46,XY DSD
38
• Maternal intake of endocrine disruptors
| – Chemicals that disrupt the endocrine system
Congenital non-genetic 46,XY DSD
39
- Common cause of male hypogonadism seen in infertility work-up
- 47,XXY
- Variants: XXXY, XXXXY, XXYY, and XXY/mosaics
- Usually from maternal nondisjunction
- Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia *(due to high E:T ratio)*, female hair distribution
- May present with developmental delay
- Increased risk for autoimmune disorders (e.g., diabetes)
- Presence of inactivated X chromosome (Barr body)
- Incr LH, Incr FSH, Decr testosterone, Decr sperm count
Klinefelter syndrome
40
- 46,XO
- Short stature (if untreated), ovarian dysgenesis *(streaked ovary)*, shield chest, bicuspid aortic valve, **coarctation of aorta**, *webbed neck or cystic hygroma*, horseshoe kidney
- MC cause of 1º amenorrhea
- Menopause before menarche
- Can result from mitotic or meiotic error
Turner syndrome
41
Must have individuals with Turner syndrome karyotype to rule out presence of Y-chromosome because the presence of y-chromosome increases the risk (95%) of:
Gonadoblastoma
| prophylactic removal of streaked ovaries
42
• “Male Turner” syndrome
• Autosomal dominant
• Mutations in PTPN11 gene (~ half of cases)
– Oncogene regulating RAS/MAPK signaling pathway
• Regulates cell proliferation, differentiation, migration, apoptosis.
• Critical in development of heart, blood cells, bones and other tissues
Noonan syndrome
43
* Delayed puberty
* Down-slanting or wide-set eyes
* Hearing loss (varies)
* Low-set or abnormally shaped ears
* Mild mental retardation(~25% of cases)
* Pulmonary stenosis***
* Ptosis
* Short stature
* Small penis
* Undescended testicles
* Pectus excavatum
* Short, webbed neck
* Fertility problems but fertile**
Noonan syndrome
44
List the essential amino acids.
"PVT TIM HALL"
```
Phenylalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histidine
Arginine
Leucine
Lysine
```
45
Findings: intellectual disability, growth retardation, seizures, fair skin/hair, eczema, musty/mousey body odor*
Dx?
What enzyme is deficient?
Which AA becomes essential?
What test is used to view PHE levels?
Phenylketonuria (type I)
Due to decreased phenylalanine hydroxylase.
Tyrosine becomes essential.
Guthrie test – bacterial inhibition assay
(Now more likely to see Mass Tandem Spec in hospitals)
46
- Insufficient BH4 (tetrahydrobiopterin cofactor) which leads to BH2 deficiency
- Due to deficiency of dihydropteridine reductase
- Major clinical finding: abnormal response to diet
- Progressive deterioration
- May respond to BH4 treatments
Dx?
Type II Hyperphenylalaninemia
| "Malignant PKU"
47
- Due to deficiency of dihydropteridine synthetase
- 1-3% of all hyperphenylalaninemia
- Progressive neuro deterioration
- May respond to BH4 tx
Type III Hyperphenylalaninemia
48
- Lack of proper dietary therapy during pregnancy
| - Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects
Maternal PKU
49
- Autosomal recessive
- Deficiency of homogentisate oxidase
- In degradative pathway of tyrosine to fumarate
- Arthritis
- Dark colored cartilage
- Urine turns black on standing
Alkaptonuria
50
- Autosomal recessive
- Unable to synthesize melanin
- Hair, skin, eyes affected
- Associated ocular defects
- Photophobia
Albinism
51
- Autosomal recessive
- Failure to thrive
- Benign, transient defect in TYR metabolism
- Defect in p-hydroxyphenylpyruvic acid oxidase
- (+) Guthrie test
Neonatal tyrosinemia
52
Defect in tyrosine aminotransferase
Hepatorenal tyrosinemia
Renal obstruction
Liver failure
Dx?
Tyrosinemia type II
53
Defect in fumarylacetoacetate hydrolase
Oculocutaneous tyrosinemia
Photophobia
Conjunctivitis
Dx?
Tyrosinemia type I
54
Albinism subtype.
| Tyrosinase (–)
Albinism type IA
55
Albinism subtype.
Tyrosinase (+)
General reduction in pigmentation
Albinism type IB
56
Albinism subtype (MC).
Tyrosinase (+)
In pigmented nevi
Hair yellow or light colored
Albinism type II
57
Findings: Increased homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus (tall, long limbs), lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke/MI)
Dx?
Deficiency of what enzyme?
Homocystinuria
Deficient enzyme: cystathionine synthase
Methionine and cysteine – sulfur groups*
(See p. 108 in FA)
58
- Defect in alpha ketoacid dehydrogenase
- Blocked degradation of branched chain amino acids (elevated leucine, isoleucine, valine)
- Seizures
- Mental retardation
Maple syrup urine disease
59
- Absence of galactose-1-phosphate uridyltransferase
- Autosomal recessive
- Damage caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye)
- Sx: failure to thrive, jaundice, hepatomegaly, infantile cataracts*** (due to increased osmotic pressure), intellectual disability
Dx?
Classic galactosemia
60
- Hereditary deficiency of galactokinase
- Autosomal recessive, relatively mild
- Sx: galactose appears in blood and urine, infantile cataracts*
- May present as failure to track objects or to develop a social smile
```
Galactokinase deficiency
(non-classical galactosemia)
```
61
TQ
What is the biggest risk factor for breast cancer?
Name some other risk factors..
```
#1: Increasing age
• Family history
• Mutations in BRCA1 and BRCA2 • Early menarche
• Nulliparity
• Late menopause
• Estrogen use
• Dietary factors
```
62
Features assoc w/ incr risk of breast and ovarian cancers?
BCRA1 & 2 mutation
TP53 mutation
PTEN mutation
HNPCC
63
What is "family clustering" of cancer?
-No evidence of Mendelian inheritance
-May be a weaker predisposition
-Non-genetic influences
• Environment
• Socioeconomic factors
• Diet
64
TQ
What are the most common genes known to cause breast and ovarian cancer?
What is their gene function, expression, and mechanism of inheritance?
BRCA1 (chr 17) and 2 (chr 13) are tumor suppressor genes:
- Control cell division (G1/S)
- DNA repair
- Apoptosis
Expressed in most tissues (G1-S) and activates p21 CDK inhibitor
65
- Recognizable motifs (ring-finer and BRCT domain + tandem repeats)
- Breast ca 50-85% (early age)
- Second primary breast ca
- Ovarian cancer (15-45%)
- Incr risk for prostate and colon cancer
What is the mutation?
BRCA1
66
- Breast Cancer
- Ovarian cancer
- Male breast cancer
- Risk of prostate, laryngeal, and pancreatic cancers
What is the mutation?
BRCA2
67
AD
- cancer predisposition syndrome
- variety of cancers within the same family
- risk of multiple primary cancers
What is the mutation?
Ex: Breast + osteosarcoma + brain tumor + leukemia
Li-Fraumeni Syndrome
TP53 (chr 17)
90% lifetime cancer risk for women
68
- Multiple hamartoma syn w/ high risk of benign and malignant tumors of the breast, **thyroid, and endometrium, GI
- Macrocephaly
- Trichilemmomas
- Papillomatous papules by LATE 20s!
- Hyperkeratosis
What is the mutation?
Cowden syndrome
PTEN (chr 10)
Usually problem in tissues that are rapidly turning over (will have GF around PIP3 sensitive)
69
- multiple colon primary tumors
- endometrial ca
- ovarian ca
What is mutated?
HNPCC (Lynch syndrome II)
Mismatch repair gene mut
MSH6 MSH2 EPCAM PMS2 MLH1
70
How does micro-satellite instability lead to ineffective repair?
Mutations in repair enzymes
Ex: HNPCC
71
- Early onset BC (<50) yo
- Early onset BC + ovarian
- Bilateral dz
- Jewish
- Male breast cancer
What is the mutation?
BRCA 1 OR 2
| AD
72
Same mutation but some individuals may not develop cancer...age of onset and type of cancer also varies...
Penetrance! (Breast and ovary)
73
T/F The longer you live w/ a BRAC mutation, the greater your risk of developing breast cancer.
TRUE
74
Which population is esp assoc with BRAC1 or 2 mutations?
- Ashkenazi Jews (1 in 100)
| - Stabilization of mutation within a population (founder mutations traced back to 600 yrs ago)
75
3 BRCA 1 and 2 mutations account for most breast ca in Jews...
What is the three mutation test?
- Focuses on the 3 specific mutations (certain deletions)
| - False negatives
76
If family member of BRCA + individual is tested for a family-specific mutation, and it is absent...are they still at risk?
YES just like general population....(1:500 to 1:1000)
77
```
TP53-->
Incr p21 (CDK inhib)
Incr GADD45 (DNA repair)-->BAX-->Apoptosis
```
Is p53 an oncogene or tumor suppressor gene?
Mode of inheritance for LiFraumeni?
- Tumor suppressor gene
| - AD
78
Role of PTEN in the cell?
Is it an oncogene or tumor suppressor gene?
Inheritance pattern in Cowden's syn?
- Dephosphorylate PIP3 to PIP2 to control growth...mutated=no dephos, upreg of oncogenes
- Tumor suppressor gene
- AD
79
- HNPCC
- Di-nucleotide repeats (CA12, 14, 16)
- Additions/deletions
- Defective mismatch repair
Microsatellite instabilty
80
GADD45 is assoc w/ what check point in the cell cycle?
G1/G2-->apoptosis via BAX
81
BAX=apoptosis pathway
BAX is part of which gene family?
How does it work?
BCL2 gene BAX controls mito apoptosis
p53-->BAX-->cyclophilin D-->membrane distruption-->apoptosis
AND
antagonize BCL2
(BCL2=survive, BAX=apoptosis)
82
Microsatellite instability:
Mononucleotide repeat G8 (loss or gain-->G6 or G7)
What does this affect?
Decr apoptosis ability by mutation BAX...
83
- A10 repeat (mononucleotide)
- Frameshift in HNPCC pts via insertions or deletions
What signaling pathway is the mutated gene involved in?
TGFBR2 gene
LAP cleavage-->R1-->R2-->signaling via SMADS*
TGFB=Multifunctional cytokine-->
SMAD-->apoptosis, prolif, or diff
