‹#›
=
Inst. of Biology and Medical Genetics, First Faculty of Medici=
ne,
Praha
Molecular genetics IV
=
![](3D"slide0056_image002.gif")
![](3D"slide0056_image004.gif")
![](3D"slide0056_image005.gif")
winter semester
Nov.
2008
![](3D"slide0067_image006.gif")
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Nondisjunction in Down syndrome
The pedigrees show families=
where
children are affected with Down syndrome <=
/b>(simple trisomy). The results of DNA analysis
are shown under pedigrees. Polymorphism
of a tetranucleotide microsatellite on chromosome 21 was determined.
From which
parent the<=
b>
affected child inherited an extra chromosome 21?
In which meiotic division the<=
b>
nondisjunction occurred?
2
![](3D"slide0058_image007.gif")
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=
=
?
Meiosis I in mother =
or
father
=
Nondisjunction in Down syndrome
3
![](3D"slide0059_image008.gif")
<=
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
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=
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
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?
Meiosis I in mother <=
span
lang=3DCS style=3D'font-family:"Comic Sans MS";mso-ascii-font-family:"Comi=
c Sans MS";
mso-hansi-font-family:"Comic Sans MS";font-size:250%;text-shadow:auto'>=
or
father
<=
span
lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
=
=
=
Meiosis
I in
Nondisjunction in Down syndrome
4
![](3D"slide0060_image009.gif")
<=
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
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?
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lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
=
=
<=
span
lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
![](3D"slide0060_image010.gif")
![](3D"slide0060_image011.gif")
Nondisjunction in Down syndrome
Meiosis I in mother <=
span
lang=3DCS style=3D'font-family:"Comic Sans MS";mso-ascii-font-family:"Comi=
c Sans MS";
mso-hansi-font-family:"Comic Sans MS";font-size:250%;text-shadow:auto'>=
or
father
=
Meiosis
I in
=
Meiosis
II in
5
DNA sequencing
External files:
http://www.dnalc.org/ddnalc/resources/ani=
mations/cycseq.exe
&#=
13;
6
![](3D"slide0064_image012.gif")
A
C
G
T
(-)
(+)
![](3D"slide0064_image013.gif")
![](3D"slide0064_image014.gif")
![](3D"slide0064_image015.gif")
![](3D"slide0064_image017.gif")
![](3D"slide0064_image018.gif")
![](3D"slide0064_image019.gif")
![](3D"slide0064_image020.gif")
![](3D"slide0064_image021.gif")
P
![](3D"slide0064_image022.gif")
![](3D"slide0064_image023.gif")
![](3D"slide0064_image024.gif")
![](3D"slide0064_image025.gif")
![](3D"slide0064_image026.gif")
![](3D"slide0064_image027.gif")
![](3D"slide0064_image028.gif")
![](3D"slide0064_image029.gif")
![](3D"slide0064_image030.gif")
![](3D"slide0064_image031.gif")
![](3D"slide0064_image032.gif")
![](3D"slide0064_image033.gif")
A
C
G
T
(-)
(+)
![](3D"slide0064_image034.gif")
![](3D"slide0064_image035.gif")
![](3D"slide0064_image036.gif")
![](3D"slide0064_image038.gif")
![](3D"slide0064_image039.gif")
![](3D"slide0064_image040.gif")
![](3D"slide0064_image041.gif")
![](3D"slide0064_image042.gif")
C
![](3D"slide0064_image043.gif")
![](3D"slide0064_image044.gif")
![](3D"slide0064_image045.gif")
![](3D"slide0064_image046.gif")
![](3D"slide0064_image047.gif")
![](3D"slide0064_image048.gif")
![](3D"slide0064_image049.gif")
![](3D"slide0064_image050.gif")
![](3D"slide0064_image051.gif")
![](3D"slide0064_image052.gif")
![](3D"slide0064_image053.gif")
FGFR2 mutation in Apert syndrome
![](3D"slide0064_image054.gif")
=
![](3D"slide0064_image055.gif")
G
7
![](3D"slide0065_image056.gif")
=
![](3D"slide0065_image057.gif")
G
<=
span
lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
250
…. ….
…. GAG CGA TCG<=
/b> CCT<=
/b> CAC<=
/b> CGG<=
/b> CCC<=
/b> ATC<=
/b>…
…. ….
Glu Arg Ser Pro His Arg Pro Ile
250
…. ….
…. GAG CGA TGG CCT<=
/b> CAC<=
/b> CGG<=
/b> CCC<=
/b> ATC<=
/b>…
…. ….
Glu Arg Trp Pro His Arg Pro Ile
![](3D"slide0065_image058.gif")
=
Ser252Trp
S252W
FGFR2 mutation in Apert syndrome
8
„Next generation“ sequencing methods, an example: SOLiD<=
/b>
![3D"SOLiD_color_decod.gif"](3D"slide0074_image060.gif")
9
SOLiD: Rewrite the sequences from color space to the =
conventional format (first base is G). Which patient sequence represents genuine mutation and which is an error?
![](3D"slide0075_image062.gif")
![](3D"slide0075_image063.gif")
![](3D"slide0075_image065.gif")
Control sequence
Patient 1
![](3D"slide0075_image066.gif")
Patient 2
![](3D"slide0075_image068.gif")
10
![](3D"slide0076_image069.gif")
![](3D"slide0076_image070.gif")
![](3D"slide0076_image071.gif")
![](3D"slide0076_image072.gif")
![](3D"slide0076_image073.gif")
![](3D"slide0076_image075.gif")
![](3D"slide0076_image076.gif")
![](3D"slide0076_image077.gif")
![](3D"slide0076_image079.gif")
![](3D"slide0076_image081.gif")
![](3D"slide0076_image082.gif")
![](3D"slide0076_image083.gif")
Patient 1 – mutation C ->
G, patient 2 – assay error, recheck necessary
11
SOLiD: Rewrite the sequences from color space to the =
conventional format (first base is G). Which patient sequence represents genuine mutation and which is an error?
Control sequence
Patient 1
Patient 2
Task 5, p. 110 &nb=
sp;
1308
…. ….
…. AAA GAA AAG ATT GGA ACT AGG TCA … …. ….=
Lys Glu Lys Ile Gly Thr Arg Ser
1315
![](3D"slide0066_image084.gif")
![](3D"slide0066_image085.gif")
…. …. …. AAA
![](3D"slide0066_image086.gif")
GAT
![](3D"slide0066_image087.gif")
TGG
![](3D"slide0066_image088.gif")
AAC
![](3D"slide0066_image089.gif")
TAG
Lys &=
nbsp;
Asp Trp Asn Term
A.
![](3D"slide0066_image090.gif")
B.
…. ….
…. GTG CAG GGT &=
#8230;
…. ….
Leu Gln Gly
1339
![](3D"slide0066_image091.gif")
Leu Term
![](3D"slide0066_image092.gif")
C.
…. ….
…. GCC AGG CAC … …. ….<=
/span>
1350
![](3D"slide0066_image093.gif")
Ala Arg Leu
![](3D"slide0066_image094.gif")
Frameshift mutation
Nonsense mutation
Missense mutation
12
Achondr=
oplasia
is the most common inhertited form of dwarfism. It was relealed, that the
cause is a mutation in FGFR3 (fibroblast growth factor receptor 3.
Approximately 95% of patients have a single mutation type – a transi=
tion
1138G>A, leading to substitution Gly380Arg in the protein. The
mutation simultaneously creates a restriction site forSfcI
![](3D"slide0068_image096.gif")
![](3D"slide0068_image097.gif")
PCR:
55bp
109bp
13
![](3D"slide0069_image100.gif")
Task: e=
valuate
the risk, that a couple, both suffering from achondroplasia, will have a c=
hild
homozygous for the mutant allele (this genotype is invariably lethal after
birth, and pregnancy may be life-threatening in some mothers with
achondroplasia). :
=
![](3D"slide0069_image101.gif")
![](3D"slide0069_image102.gif")
=
=
=
![](3D"slide0069_image104.gif")
=
=
164
=
109
55
Shiang et al., 1994
14
![](3D"slide0069_image106.gif")
![](3D"slide0077_image109.gif")
=
![](3D"slide0077_image110.gif")
![](3D"slide0077_image111.gif")
=
=
=
![](3D"slide0077_image113.gif")
=
=
164
=
109
55
Shiang et al., 1994
![3D"ach_gel.png"](3D"slide0077_image115.gif")
15
Task: e=
valuate
the risk, that a couple, both suffering from achondroplasia, will have a c=
hild
homozygous for the mutant allele (this genotype is invariably lethal after
birth, and pregnancy may be life-threatening in some mothers with
achondroplasia). :
![](3D"slide0070_image116.gif")
![](3D"slide0070_image119.gif")
=
![](3D"slide0070_image120.gif")
![](3D"slide0070_image121.gif")
=
<=
span
lang=3DCS style=3D'mso-special-format:lastCR;display:none'>
=
![](3D"slide0070_image123.gif")
=
=
164
=
109
55
Shiang et al., 1994
Solutio=
n: both
parents are heterozygous for G380R, as well as the father of the pregnant
mother. DNA of the fetus contains only the allele with the restriction sit=
e,
i.e. mutant allele, so the fetus is homozygous (AA) and pregnancy interrup=
tion
is recommended. Note: in father´s family we see a new mutation arisi=
ng
(both parents healthy).
![](3D"slide0070_image124.gif")
aa
aa
Aa
Aa
Aa
aa
AA
16
In few
patients, achondroplasia is caused by a different mutation in FGFR3 gene, =
in
the same codon, 1138G>C.
b) Desi=
gn a
direct DNA diagnostic method to identify this mutation: further infromatio=
ns
on website of the Institute (click he=
re)
17
![](3D"slide0073_image125.gif")
digest
<=
/span>
enzyme&=
#13;
fragment length(kb)
1.
Pst I&=
#13;
6.4 + 3.6&=
#13;
2.
Bgl II&=
#13;
8.8 + 1.2 &=
#13;
3.
Pst I and Bgl II&=
#13;
5.2 + 3.6 + 1.2&=
#13;
DNA seq=
uence,
10kb long, contains one cleavage site for restriction endonuclease PstI and
one for Bgl II. Three independent reactions were performed:
Task 3, p. 113 &nb=
sp;
18
![](3D"slide0063_image126.gif")
10 kb
<=
/div>
![](3D"slide0063_image127.gif")
3.6 kb
Pst I
![](3D"slide0063_image130.gif")
6.4 kb
![](3D"slide0063_image131.gif")
1.2 kb
Bgl II
=
![](3D"slide0063_image134.gif")
8.8 kb
![](3D"slide0063_image135.gif")
3.6 kb
Pst I + Blg II
5.2 kb
1.2 kb
![](3D"slide0063_image136.gif")
=
![](3D"slide0063_image137.gif")
1.2 kb
3.6 kb
Pst I + Blg II
=
5.2 kb
![](3D"slide0063_image138.gif")
3.6 kb
Pst I + Blg II
5.2 kb
1.2 kb
19
Task 5, p. 131 &nb=
sp;
The exa=
mination
is a Southern blot hybridized with a probe against high-frequency repetiti=
ve
sequence (minisatellite type). Different length alleles of multiple loci m=
erge
in a individual-specific pattern (this method is little bit out of fashion
now).
![](3D"slide0072_image140.gif")
20
![](3D"slide0072_image141.gif")
Klepnutím lze upravit styly předlohy textu.
=
Druhá úroveň
Třetí úroveň
Čtvrtá úroveň
Pátá úroveň
‹#›
11<=
/div>
Position 380 is in the transmembrane domain=
of the
protein, and arginin at this place leads to increas=
ed
dimerization of the receptor and thus increased FGF
signaling. The result is increased apoptosis of chondrocytes in the xxx of the long bones.
The assay is simply PCR with primers flanki=
ng the
mutation site, with subsequent cleavage of the PCR
product by SfcI. Without mutation, the DNA 164 bp
fragment remains uncleaved, with mutation you expect two fragments:
55 and 109 bp.
13<=
/div>
Your task is to counsel this family. Both p=
arents
have achondroplasia, so there is 25% risk that their
child will be dominant homozygote. Since dominant
homozygotes don´t survive perinatal period, and pregnancy is =
threatening for the mother, interruption will be recommended in =
that
case.
So determine the genotype of the individual=
s in the
family, and specifically of the child.
<=
/div>
Second, explain where the father got his
achondroplasia from.
14<=
/div>
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