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High resolution mapping of the X chromosome pseudoautosomal region in two siblings with Hodgkin Lymphoma and Leri-Weill Dyschondrosteosis. Kym Spencer Liverpool Women’s Hospital. Reed-Sternberg cells & Hodgkin cells. Clinical Features. Incidence. Cancer Research UK figures for 2004: - PowerPoint PPT Presentation
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High resolution mapping of the X chromosome pseudoautosomal region in two siblings with Hodgkin Lymphoma and Leri-Weill Dyschondrosteosis
Kym Spencer
Liverpool Women’s Hospital
Reed-Sternberg cells & Hodgkin cells
Clinical Features
Incidence
Cancer Research UK figures for 2004:1,519 new cases - 0.5% of all cancers
diagnosed.Incidence of 2.4/100,000 individuals
2.7/100,000 males2.1/100,000 females
Bimodal age of incidence15-40 years>55 years
A genetic cause of HL
Several familial cases of HL reported.Risk of HL higher in individuals with a family history of
the condition.Higher in siblings.Highest in gender concordant siblings.Combination of inherited susceptibility with shared
environment?
Male predominance of HL Horwitz & Weirnik (1999 & 2007) suggest pseudoautosomal
link due to recombination mechanism of pseudoautosomal regions.
Family L
2 (PL) 3 (JW) 1 (ML)
1 (RL)
2 (GW)
2 (GL) 3 (RW)
4 (GW)
4 (NW)
LWD
HL
I
II
III
Leri-Weill Dyschondrosteosis (LWD)
Hodgkin Lymphoma (HL)
LWD - Madelung Deformity
Pseudoautosomal Regions
X Y
PAR1
PAR2
p
p
q
q
Map of PAR1
Tel
omere
100 300 200
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
DXYS
Microsatellite markers
2726
-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
Family L
LWD
HL
2 (PL) 3 (JW) 1 (ML)
1 (RL) 2 (GL) 3 (RW)
4 (GW)
4 (NW)
I
II
III
Leri-Weill Dyschondrosteosis (LWD)
Hodgkin Lymphoma (HL)2 (GW)
Methods
MLPA for SHOX copy number using P018B MLPA kit from MRC Holland
Fluorescent microsatellite analysisAddition of custom probes into existing
MLPA kitSNP analysisMicroarray analysis
SHOX MLPA
DE
L
C1
5q31
C2
16p1
3
C3
20q1
1
C4
9q34
C5
13q1
4
C6
8q24
C7
18q2
1
C8
13q1
2
C9
2p22
C10
10p
14
PP
P2R
3B
LOC
1590
15
SH
OX
Ex1
SH
OX
Ex2
SH
OX
Ex3
SH
OX
Ex4
SH
OX
Ex5
SH
OX
Ex6
SH
OX
Ex7
SH
OX
Ex8 PA
R 5
642-
L509
6
PA
R 5
643-
L509
7
PA
R 5
644-
L509
8
PA
R 5
645-
L509
9
PA
R 5
646-
L510
0
PA
R 5
647-
L510
1
PA
R 6
291-
L622
2
PA
R 6
292-
L580
1
PA
R 6
293-
L621
9
PA
R 5
648-
L621
8
PA
R 5
649-
L510
3
PA
R 5
650-
L510
4
PA
R 5
651-
L510
5
CS
F2R
A
IL3R
A
PA
R 5
652-
L510
6
AS
MT
AR
SF
GP
R14
3
GP
R14
3(ii)
Xq2
5
SY
BL1
SM
CY
SR
Y
DB
Y
0.00
0.20
0.40
0.60
0.80
1.00
1.20
RL
C1
5q31
C2
16p1
3C
3 20
q11
C4
9q34
C5
13q1
4C
6 8q
24C
7 18
q21
C8
13q1
2
C9
2p22
C10
10p
14P
PP
2R3B
LOC
1590
15
SH
OX
Ex1
SH
OX
Ex2
SH
OX
Ex3
SH
OX
Ex4
SH
OX
Ex5
SH
OX
Ex6
SH
OX
Ex7
SH
OX
Ex8
PA
R 5
642-
L5096
PA
R 5
643-
L5097
PA
R 5
644-
L5098
PA
R 5
645-
L5099
PA
R 5
646-
L5100
PA
R 5
647-
L5101
PA
R 6
291-
L6222
PA
R 6
292-
L5801
PA
R 6
293-
L6219
PA
R 5
648-
L6218
PA
R 5
649-
L5103
PA
R 5
650-
L5104
PA
R 5
651-
L5105
CS
F2R
AIL
3RA
PA
R 5
652-
L5106
AS
MT
AR
SF
GP
R14
3G
PR
143(ii
)
Xq25
SY
BL1
SM
CY
SR
YD
BY
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
ML
C1 5
q31
C2 1
6p13
C3 2
0q11
C4 9
q34
C5 1
3q14
C6 8
q24
C7 1
8q21
C8 1
3q12
C9 2
p22
C10 1
0p14
PP
P2R
3B
LO
C159015
SH
OX
Ex1
SH
OX
Ex2
SH
OX
Ex3
SH
OX
Ex4
SH
OX
Ex5
SH
OX
Ex6
SH
OX
Ex7
SH
OX
Ex8
PA
R 5
642-L
5096
PA
R 5
643-L
5097
PA
R 5
644-L
5098
PA
R 5
645-L
5099
PA
R 5
646-L
5100
PA
R 5
647-L
5101
PA
R 6
291-L
6222
PA
R 6
292-L
5801
PA
R 6
293-L
6219
PA
R 5
648-L
6218
PA
R 5
649-L
5103
PA
R 5
650-L
5104
PA
R 5
651-L
5105
CS
F2R
A
IL3R
A
PA
R 5
652-L
5106
AS
MT
AR
SF
GP
R143
GP
R143(ii)
Xq25
SY
BL1
SM
CY
SR
Y
DB
Y
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
SHOX MLPA
Tel
omere
100 200
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
2726
-L1588 (PPP2R3B exon 5)
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Key Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
DXYS
Microsatellite markers
2726
-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
PPP2R3B
PPP2R3B encodes PR48. B subunit of the PP2A holoenzyme. Involved in cell cycle regulation - binds to Cdc6 in mammalian
cells and restricts DNA replication.
PP2A is a cell cycle regulator and tumour suppressor. Consists of A, B and C subunits. B subunits confer substrate specificity.
A
B
C
B’
B’’
B’’’
PR65α or β
PP2A
PR55α, β, γ or δ
PR61α, β, γ, δ or ε
PR72/PR130 or PR48
PR93/SG2NA or PR110/striatin
α or β
Microsatellite Analysis
111+23
--- ∆ --
--- ∆ --
RL GL
221+12
221+11
221+12
111+23
221+11
331+24
--- ∆ --
ML PL
GW
DXYS10037 DXYS10038 DXYS10039 SHOX DXYS10180 DXYS10181
LWD
HL
Microsatellite Analysis
Tel
omer
e
100 300 200 400
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
2726-L1588 (P
PP
2R3B
exon 5)
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Key Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
D
XY
S
Microsatellite markers
2726-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
Custom MLPA
DE
L
C1
5q
31
C2
16
p1
3C
3 2
0q
11
C4
9q
34
C5
13
q1
4C
6 8
q2
4C
7 1
8q
21
C8
13
q1
2C
9 2
p2
2C
10
10
p1
4P
PP
2R
3B
Ex
5P
PP
2R
3B
Ex
4P
PP
2R
3B
Ex
1L
OC
15
90
15
SH
OX
Ex1
SH
OX
Ex2
SH
OX
Ex3
SH
OX
Ex4
SH
OX
Ex5
SH
OX
Ex6
SH
OX
Ex7
SH
OX
Ex8
PA
R 5
64
2-L
50
96
PA
R 5
64
3-L
50
97
PA
R 5
64
4-L
50
98
PA
R 5
64
5-L
50
99
PA
R 5
64
6-L
51
00
PA
R 5
64
7-L
51
01
PA
R 6
29
1-L
62
22
PA
R 6
29
2-L
58
01
PA
R 6
29
3-L
62
19
PA
R 5
64
8-L
62
18
PA
R 5
64
9-L
51
03
PA
R 5
65
0-L
51
04
PA
R 5
65
1-L
51
05
CS
F2
RA
IL3
RA
PA
R 5
65
2-L
51
06
AS
MT
AR
SF
GP
R1
43
GP
R1
43
(ii)
Xq
25
SY
BL
1S
MC
YS
RY
DB
Y
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
RL
C1
5q
31
C2
16
p1
3C
3 2
0q
11
C4
9q
34
C5
13
q1
4C
6 8
q2
4C
7 1
8q
21
C8
13
q1
2C
9 2
p2
2C
10
10
p1
4P
PP
2R
3B
Ex
5P
PP
2R
3B
Ex
4P
PP
2R
3B
Ex
1L
OC
15
90
15
SH
OX
Ex1
SH
OX
Ex2
SH
OX
Ex3
SH
OX
Ex4
SH
OX
Ex5
SH
OX
Ex6
SH
OX
Ex7
SH
OX
Ex8
PA
R 5
64
2-L
50
96
PA
R 5
64
3-L
50
97
PA
R 5
64
4-L
50
98
PA
R 5
64
5-L
50
99
PA
R 5
64
6-L
51
00
PA
R 5
64
7-L
51
01
PA
R 6
29
1-L
62
22
PA
R 6
29
2-L
58
01
PA
R 6
29
3-L
62
19
PA
R 5
64
8-L
62
18
PA
R 5
64
9-L
51
03
PA
R 5
65
0-L
51
04
PA
R 5
65
1-L
51
05
CS
F2
RA
IL3
RA
PA
R 5
65
2-L
51
06
AS
MT
AR
SF
GP
R1
43
GP
R1
43
(ii)
Xq
25
SY
BL
1S
MC
YS
RY
DB
Y
0.00
0.20
0.40
0.60
0.80
1.00
1.20
ML
C1
5q
31
C2
16
p1
3C
3 2
0q
11
C4
9q
34
C5
13
q1
4C
6 8
q2
4C
7 1
8q
21
C8
13
q1
2C
9 2
p2
2C
10
10
p1
4P
PP
2R
3B
Ex
5P
PP
2R
3B
Ex
4P
PP
2R
3B
Ex
1L
OC
15
90
15
SH
OX
Ex1
SH
OX
Ex2
SH
OX
Ex3
SH
OX
Ex4
SH
OX
Ex5
SH
OX
Ex6
SH
OX
Ex7
SH
OX
Ex8
PA
R 5
64
2-L
50
96
PA
R 5
64
3-L
50
97
PA
R 5
64
4-L
50
98
PA
R 5
64
5-L
50
99
PA
R 5
64
6-L
51
00
PA
R 5
64
7-L
51
01
PA
R 6
29
1-L
62
22
PA
R 6
29
2-L
58
01
PA
R 6
29
3-L
62
19
PA
R 5
64
8-L
62
18
PA
R 5
64
9-L
51
03
PA
R 5
65
0-L
51
04
PA
R 5
65
1-L
51
05
CS
F2
RA
IL3
RA
PA
R 5
65
2-L
51
06
AS
MT
AR
SF
GP
R1
43
GP
R1
43
(ii)
Xq
25
SY
BL
1S
MC
YS
RY
DB
Y
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
Custom MLPA
Tel
omer
e
100 300 200 400
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
2726-L1588 (PP
P2R3B
exon 5)
PP
P2R
3B exon 1 C
ustom
PP
P2R
3B exon 4 C
ustom
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Key Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
D
XY
S
Microsatellite markers
2726-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
SNP Analysis
ML
RL
PL
GW
GL
PPP2R3B + +rs4986484 G/T G Grs5991323 G/A G Grs4986485 A/G A Ars4986486 C/T C Crs4131267 G/A G Grs6645040 C/T C Crs4986487 A/T A Ars6645077 G/A G -rs6644996 A/G A -rs28715562 A/G A -rs28418955 G/A G -rs6644997 T/C T -rs6645078 C/T C -rs28491143 G/T G -rs28393142 T/C T -rs35933458 C/T C -rs35741392 C/G C -rs6645016 G/A A -rs6645017 G/C C -rs28430679 C/T C -SHOX + -
LWD
HL
PPP2R3B + +rs4986484 G/T G Trs5991323 G/A G Grs4986485 A/G A Grs4986486 C/T C Trs4131267 G/A G Ars6645040 C/T C Trs4986487 A/T A Trs6645077 G/A G Grs6644996 A/G A Ars28715562 A/G G Ars28418955 G/A A Grs6644997 T/C C Trs6645078 C/T C Crs28491143 G/T T Grs28393142 T/C C Trs35933458 C/T C Crs35741392 C/G C Crs6645016 G/A A Grs6645017 G/C C Grs28430679 C/T C CSHOX + +
PPP2R3B + +rs4986484 G/T G Grs5991323 G/A G Grs4986485 A/G A Ars4986486 C/T C Crs4131267 G/A G Grs6645040 C/T C Crs4986487 A/T A Ars6645077 G/A G -rs6644996 A/G A -rs28715562 A/G G -rs28418955 G/A A -rs6644997 T/C C -rs6645078 C/T C -rs28491143 G/T T -rs28393142 T/C C -rs35933458 C/T C -rs35741392 C/G C -rs6645016 G/A A -rs6645017 G/C C -rs28430679 C/T C -SHOX + -
PPP2R3B + +rs4986484 G/T T Grs5991323 G/A G Grs4986485 A/G G Ars4986486 C/T T Crs4131267 G/A A Grs6645040 C/T T Crs4986487 A/T T Ars6645077 G/A G -rs6644996 A/G A -rs28715562 A/G A -rs28418955 G/A G -rs6644997 T/C T -rs6645078 C/T C -rs28491143 G/T G -rs28393142 T/C T -rs35933458 C/T C -rs35741392 C/G C -rs6645016 G/A G -rs6645017 G/C G -rs28430679 C/T C -SHOX + -
PPP2R3B + +rs4986484 G/T G Grs5991323 G/A G Grs4986485 A/G A Ars4986486 C/T C Crs4131267 G/A G Grs6645040 C/T C Crs4986487 A/T A Ars6645077 G/A G Grs6644996 A/G A Ars28715562 A/G A Grs28418955 G/A G Ars6644997 T/C T Crs6645078 C/T C Crs28491143 G/T G Trs28393142 T/C T Crs35933458 C/T C Crs35741392 C/G C Crs6645016 G/A A Grs6645017 G/C C Grs28430679 C/T C CSHOX + +
SNP Analysis
Tel
omer
e
100 300 200 400
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
2726-L1588 (P
PP
2R3B
exon 5)
PP
P2R
3B exon 1 C
ustom
PP
P2R
3B exon 4 C
ustom
282kb – 7 SNP
s
355kb – 8 SNP
s
445kb – 6 SNP
s
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Key Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
D
XY
S
Microsatellite markers
2726-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
CTCF
Tel
omer
e
100 300 200 400
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
2726-L1588 (P
PP
2R3B
exon 5)
PP
P2R
3B exon 1 C
ustom
PP
P2R
3B exon 4 C
ustom
282kb – 7 SNP
s
355kb – 8 SNP
s
445kb – 6 SNP
s
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Key Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
D
XY
S
Microsatellite markers
2726-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted CTCF
Binding site
CTCF CTCF (CCCTC - binding factor) Transcriptional regulator through
chromatin remodelling epigenetic modification control of transcriptional machinery insulating promoter interaction with enhancers /silencers
Can bind to a diverse array of DNA sequences using different combinations of its 11 zinc finger domains
CTCF zinc finger domain
More SNP analysis
ML
RL
PL
GW
GL
LWD
HL
PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T C Trs28536695 C/G C Crs5950823 G/T T Trs5950824 C/T T Crs5950825 C/G C Crs5950826 A/G G G
CTCF + +rs28421260 G/A A Ars5991174 G/C G Grs5950684 G/A A Ars5950685 C/T T Trs34943375 A/G A Ars5950834 G/A G Grs5950686 C/G G Grs5950835 A/G G Grs7473428 A/G A A
SNPs @ 355kb + +SNPs @ 445kb + +SHOX + +
PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T C T
rs28536695 C/G C -rs5950823 G/T T -rs5950824 C/T T -rs5950825 C/G C -rs5950826 A/G G -CTCF + -rs28421260 G/A A -rs5991174 G/C G -rs5950684 G/A A -rs5950685 C/T T -rs34943375 A/G A -rs5950834 G/A G -rs5950686 C/G G -rs5950835 A/G G -rs7473428 A/G A -SNPs @ 355kb + -SNPs @ 445kb + -SHOX + -
PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T C T
rs28536695 C/G C C
rs5950823 G/T G T
rs5950824 C/T C T
rs5950825 C/G C C
rs5950826 A/G G A
CTCF + +rs28421260 G/A A G
rs5991174 G/C G G
rs5950684 G/A A G
rs5950685 C/T T C
rs34943375 A/G A G
rs5950834 G/A G A
rs5950686 C/G G Crs5950835 A/G G A
rs7473428 A/G A G
SNPs @ 355kb + +SNPs @ 445kb + +SHOX + +
PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T C T
rs28536695 C/G C -rs5950823 G/T G -rs5950824 C/T C -rs5950825 C/G C -rs5950826 A/G G -CTCF + -rs28421260 G/A A -rs5991174 G/C G -rs5950684 G/A A -rs5950685 C/T T -rs34943375 A/G A -rs5950834 G/A G -rs5950686 C/G G -rs5950835 A/G G -rs7473428 A/G A -SNPs @ 355kb + -SNPs @ 445kb + -SHOX + -
PPP2R3B + +SNPs @ 282kb + +rs7060857 C/G G Grs7060861 A/G G Grs7060992 C/G G Grs7061128 G/T G Grs35803036 A/G G Grs34424779 G/T G Grs7061154 A/G G Grs6603263 C/T T T
rs28536695 C/G C -rs5950823 G/T T -rs5950824 C/T T -rs5950825 C/G C -rs5950826 A/G A -CTCF + -rs28421260 G/A G -rs5991174 G/C G -rs5950684 G/A G -rs5950685 C/T C -rs34943375 A/G G -rs5950834 G/A A -rs5950686 C/G C -rs5950835 A/G A -rs7473428 A/G G -SNPs @ 355kb + -SNPs @ 445kb + -SHOX + -
Microarray analysis
Tel
omer
e
100 300 200 400
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
2726-L1588 (PP
P2R
3B exon 5)
PP
P2R
3B exon 1 C
ustom
PP
P2R
3B exon 4 C
ustom
282kb – 7 SNP
s
355kb – 8 SNP
s
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
RP13-465B17
Key Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
D
XY
S
Microsatellite markers
2726-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
309kb – 9 SN
Ps
CTCF Binding site
305kb – 5 SN
Ps
300kb – 9 SN
Ps
Conclusions
Deletion of this CTCF binding site could affect regulation of its target gene.
Could the target be PPP2R3B?Deregulation of PPP2R3B could result in
deregulation of the cell cycleAnother B subunit of PP2A is present at 4p16.1, a
region linked to HL in a study by Goldin et al. (2006).
The CTCF binding site could regulate another, more distant gene.
Further studies required.
Map of PAR1
Tel
omere
100 300 200
PLCXD1
GTPBP6 (PGPL)
PPP2R3B
LLNOYCO3’M’2E2
LLNOYCO3’M’56G10
Not deleted (Shears et al 2003)
Deleted – (Shears et al.2003)
Not deleted – (present study)
Deleted – (present study)
100
Distance from telomere (kb)
Gene
FISH probe (approx. location)
Direction of transcription
DXYS
Microsatellite markers
2726
-L1588
MLPA probes
* Deleted in IC - (present study)
RP13-465B17
RP13-391G2
Microarray probes:
Not deleted Deleted
Conclusions
Deletion of this CTCF binding site could affect regulation of its target gene.
Could the target be PPP2R3B?Deregulation of PPP2R3B could result in
deregulation of the cell cycleAnother B subunit of PP2A is present at 4p16.1, a
region linked to HL in a study by Goldin et al. (2006).
The CTCF binding site could regulate another, more distant gene.
Further studies required.
AcknowledgementsThanks to the following people for their help: David Gokhale Vicky Stinton G Malcolm Taylor Ciaron McAnulty Frances White Una Maye Julie Sibbring Emma McCarthy Roger Mountford Andrew Wallace Simon Thomas Kevin Baker Gareth Evans John Radford All at Liverpool Molecular Genetics Laboratory for their help, advice, interest
and patience.
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