![](3D"slide0001_image003.gif")
Developmental
genetics
1
Drahomíra Křenová, František
Liška
December 8th – 12th, 2008
Institute of Biology and Medical Genetics
Lesson from an
experimental
animal model
![](3D"slide0002_image004.jpg")
2
![](3D"slide0003_image006.gif")
![](3D"slide0003_image010.gif")
![](3D"slide0003_image012.gif")
![](3D"slide0003_image014.gif")
![](3D"slide0003_image016.gif")
![](3D"slide0003_image017.gif")
PD
LEW.Lx
BN.Lx
![](3D"slide0003_image019.gif")
![](3D"slide0003_image021.gif")
LEW
3
Task 1, page 159, Phenotypes of polydactylous rats
![](3D"slide0004_image022.gif")
Production of LEW.Lx<=
span
style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-hansi-font-fami=
ly:
Arial;font-size:133%;text-shadow:auto;color:navy'> congenic strain =
LEW (+/+)
ND
PD (Lx/Lx)
PDL
0
1
2
3
4
24
25
24
4
recessive
![](3D"slide0004_image024.gif")
autosomal
![](3D"slide0005_image025.gif")
Production of BN.=
Lx<=
span
style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-hansi-font-fami=
ly:
Arial;font-size:133%;text-shadow:auto;color:navy'> congenic strain =
BN (+/+)
ND
PD (Lx/Lx)
PDL
0
1
2
14
N14 F2
N14 F1
5
dominant,
but incomplete penetrance
![](3D"slide0006_image033.gif")
![](3D"slide0006_image035.gif")
Phenotypes of polydactylous rats, continued
F1 hybrids
ND =3D normal digits (“normodactyly”)
=
PD =3D polydactyly
6
5T =3D 5 digits, but triphalangeal thumb
![](3D"slide0007_image037.gif")
thymidine
Teratogenic effect of a mutagenic drug
=
task
2, page 164
LEW&#=
13;
(+/+)=
LEW&#=
13;
(+/+)=
![](3D"slide0007_image038.gif")
♀
♂
X
![](3D"slide0007_image039.gif")
12th embryonic day
5-BrdU
![](3D"slide0007_image041.gif")
![](3D"slide0007_image043.gif")
5-BrdU -=
enol
![](3D"slide0007_image045.gif")
cytidine
![](3D"slide0007_image046.gif")
![](3D"slide0007_image049.gif")
7
![](3D"slide0008_image050.gif")
![](3D"slide0008_image051.gif")
How d=
o we
call this result of drug action?
What phenotype do you expect
in offspring of the drug-induced
polydactylous rats?
PHENOCOPY
NORMAL
Teratogenic effect of a mutagenic drug
=
task
2, page 164
8
Interaction of a mutant allele with a teratogen
task 3,
page 164
LEW.Lx
(Lx/Lx)
LEW&#=
13;
(+/+)=
![](3D"slide0009_image052.gif")
♀
♂
=
;
X
![](3D"slide0009_image053.gif")
no
treatment
during
pregnancy
![](3D"slide0009_image054.gif")
100%
normal
![](3D"slide0009_image055.gif")
9
Interaction of a mutant allele with a teratogen
task 3,
page 164
LEW.Lx
(Lx/Lx)
LEW&#=
13;
(+/+)=
![](3D"slide0010_image056.gif")
♀
♂
=
;
X
![](3D"slide0010_image057.gif")
12th embryonic day
5-BrdU
![](3D"slide0010_image058.gif")
![](3D"slide0010_image059.gif")
![](3D"slide0010_image060.gif")
10
![](3D"slide0011_image061.gif")
Interaction of a mutant allele with a teratogen
task 3,
page 164
ND
x ND
ND
x PD
PD
x PD
=
What
limb phenotype do we expect in offspring?
![](3D"slide0011_image063.gif")
genot=
ypes
of
parents:
+/Lx X=
+/Lx
+/Lx X=
+/Lx
+/Lx X=
+/Lx
![](3D"slide0011_image064.gif")
offspring
phenotypes:
25%
PD
25%
PD
25%
PD
11
Examples of human
inherited
developmental disorders<=
/span>
Teratogenic effect of thalidomide
=
task
1, page 165
sedative
drug thalidomide administered during pregnancy
![](3D"slide0013_image066.gif")
➔limb abnormalities (amelia)
➔oesophagus atresia
➔kidney agenesis
➔etc.
One d=
rug,
wide variety of malformations - why?
-“=
;critical
periods” of organ development
Why w=
ere
only 10-50% babies in risk malformed?
- genet=
ic
factors conferring different susceptibility<=
/div>
Why was the teratogenic effect not revealed during
preclinical
-
species-dependent susceptibility – use more species for testing!
13
Incontinentia pigmenti (sy. Bloch-Schulzberger)
task 2,
page 165
14
![](3D"slide0014_image067.jpg")
![](3D"slide0014_image070.gif")
➔ only women
afflicted
➔ vesiculous
exanthema in babies
➔ cerebral
infarctions leading to
mental retardation
➔ marble-ca=
ke
like skin (older age)
➔ many other
symptoms
➔ offspring=
of
affected females – distorted sex ratio
boys:girls 1:2, many early
abortions
What<=
/span>´s the type of inheritance?<=
/span>
X-linked dominant
lethal in males
![](3D"slide0014_image073.gif")
Incontinentia pigmenti (sy. Bloch-Schulzberger)
task 2,
page 165
15
Pathogenesis:
NEMO
IKK-=
γ
NF-=
κB
TNF-=
α
induced apoptosis
![](3D"slide0015_image074.gif")
![](3D"slide0015_image075.gif")
cells viable<=
/div>
+
NEMO
IKK-=
γ
NF-=
κB
TNF-=
α
induced apoptosis
![](3D"slide0015_image076.gif")
XIPY or XIPX+ cells with X<=
span
style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil=
y:
Arial;mso-hansi-font-family:Arial;font-size:67%;color:black;position:relat=
ive;
top:-.49em;mso-text-raise:33%'>+ lyonized
DIE
- lethal for hemizygous males
- pathogenic for carrier females
+
![](3D"slide0015_image077.gif")
![](3D"slide0015_image078.gif")
Complete androgen insensitivity syndrome
=
task
3, page 166
16
➔ female phenotype, but:
➔ primary
amenorrhea
➔ uterus and
oviducts absent
➔ no pubic =
and
axillary hair
➔ karyotype=
46,
XY
➔ undescend=
ed
testes
➔ cells
insensitive to testosterone
Only =
50%
cells of the mother
sensi=
tive
to testosterone - WHY?
X-linked
![](3D"slide0016_image079.jpg")
![](3D"slide0016_image080.gif")
XtfX+
X+
Xtf
r=
andom
X inactivation
50% sensitive
50% resistant
Complete androgen insensitivity syndrome
=
task
3, page 166
17
➔ female phenotype, but:
➔ primary
amenorrhea
➔ uterus and
oviducts absent
➔ no pubic =
and
axillary hair
➔ karyotype=
46,
XY
➔ undescend=
ed
testes
➔ cells
insensitive to testosterone
➔ only 50% =
cells
of the mother
sensitive to testosterone
What<=
/span>´s the mode of inheritance?<=
/span>
![](3D"slide0017_image082.gif")
X-linked recessive
![](3D"slide0017_image083.gif")
Complete androgen insensitivity syndrome
=
task
3, page 166
18
Why testes develop despite androgen resistance?
gonad
differentiation depends on SRY gene on Y chromosome
testost=
erone
is responsible for descent, and
pubertal changes
![](3D"slide0018_image084.gif")
Y-chromosome
SRY gene
Serto=
li
cell
germ
cells
sperm=
atogonia
AMH
uteru=
s
ovidu=
cts
Leydig
cells
testo=
sterone
IN=
SL3
androge=
n
recepto=
r
puber=
ty
![](3D"slide0018_image085.gif")
Anhidrotic ectodermal dysplasia
=
task
4, page 166
19
![](3D"slide0019_image086.jpg")
In
males:
➔ missing s=
weat
glands
➔ hypertermia
➔ serious c=
ourse
of (otherwise banal) infections
➔ abnormal
dentition
In
females:
➔ missing s=
weat
glands, in patches
➔ the patte=
rn of
skin without sweat glands differs between
monozygotic twins
What´s the mode of inheritance?
![](3D"slide0019_image088.gif")
X-linked
Anhidrotic ectodermal dysplasia
=
task
4, page 166
20
In
males:
➔ missing s=
weat
glands
➔ hypertermia
➔ serious c=
ourse
of (otherwise banal) infections
➔ abnormal
dentition
In
females:
➔ missing s=
weat
glands, in patches
➔ the patte=
rn of
skin without sweat glands differs between
monozygotic twins
Why is there different pattern in female monozygotic twins?
- Random X inactivation
Are there any differences between male monozygotic twins?
- no, they´ve no sweat glands at all
(hemizygotes for X chromosome with mutant gene)
![](3D"slide0021_image089.gif")
![3D"eda_structure_sm.jpg"](3D"slide0021_image091.gif")
' + ENDSHOW_MESG + '
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známky![](3D"buttons.gif")
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