Download Localization of CSNBX (CSNB4) between the retinitis

Localization of CSNBX (CSNB4) Between the Retinitis
Pigmentosa Loci RP2 and RP3 on Proximal Xp
Alison J. Hardcastle,* Zoe K. David-Gray* Marcelle Jay,-f Alan C. Bird,^;
and Shomi S. Bhattacharya*
Purpose. Proximal Xp harbors many inherited retinal disorders, including retinitis pigmentosa
(RP) and congenital stationary night blindness, both of which display genetic heterogeneity.
X-linked congenital stationary night blindness (CSNBX) is a nonprogressive disease causing
night blindness and reduced visual acuity. Distinct genetic loci have been reported for CSNBX
at Xp21.1, which is potentially allelic with the RP3 gene, and at Xpll.23, which is potentially
allelic with the RP2 gene. The study to identify the RP2 gene led to an extended study of
families with potentially allelic diseases that include CSNBX.
Methods. Haplotype analysis of a family diagnosed with CSNBX was performed with 17 polymorphic markers on proximal Xp covering previously identified loci for CSNBX and XLRP. Twopoint and multipoint lod scores were calculated.
Results. Informative recombinations in this family define a locus for CSNBX (CSNB4) with
flanking markers DXS556 and DXS8080 on Xpll.4 to Xpll.3, an interval spanning approximately 5 to 6 cM. A maximum lod score of 3.2 was calculated for the locus order DXS5561 cM-(CSM*4-DXS993)-2 cM-DXS1201.
Conclusions. The results describe a new localization for CSNBX (CSNB4) between the /?P2and
RP3\oc\ on proximal Xp. CSNB4 is not allelic with any previously reported XLRP loci; however,
the interval overlaps the locus reported to contain the cone dystrophy (C0D1) gene, and
both diseases are nonrecombinant with DXS993. Because mutations in the RPGR gene to
date account for disease in only a small proportion of RP3 families, the possibility that this
new locus (CSNB4) also segregates with an as yet unidentified XLRP locus cannot be excluded.
Invest Ophthalmol Vis Sci. 1997;38:2750-2755.
C^ongenital stationary night blindness (CSNB) denotes a series of nonprogressive retinal disorders inherited in an autosomal dominant (adCSNB), autosomal recessive (arCSNB), and an X-linked (CSNBX)
form. CSNBX is associated with myopia and decreased
visual acuity and is believed to result from defective
neurotransmission between photoreceptors and bipolar cells.1"3 Night blindness is also a well characterized
early clinical feature of the progressive degenerative
retinal disease retinitis pigmentosa (RP), and the func-
From the * Departments of Molecular Genetics and f Clinical Ophthalmology,
Institute of Ophthalmology, London, United Kingdom.
Supported in pan by the Welcome Trust ([AJlf] grant
04019/Z/94/Z/WRE/MB/
JAT), and by the Ulverscroft Foundation.
Submitted for publication February 7, 1997; revised July 25, 1997; accepted July
28, 1997.
Profmetary interest category: N.
Reprint requests: Alison J. Hardcastle, Department of Molecular Genetics, Institute
of Ophthalmology, University College London, 11-43 Bath Street, London, ECP/
9EL, UK.
2750
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tional relationship between RP and CSNB has been
highlighted in studies describing mutations in the
same gene that result in an RP or a CSNB phenotype.
Autosomal dominant CSNB and RP (adRP) are associated with mutations in the rhodopsin (RHO) gene on
chromosome 3p,4'5 and mutations in the gene for the
phosphodiesterase /?-subunit (PDEP) on chromosome
4p result in autosomal dominant CSNB (CSNB3)G or
in autosomal recessive retinitis pigmentosa (arRP). 7
Genetic analyses of CSNBX families during the
past decade have clearly established the heterogeneity
of this disorder, implicating at least two genes on the
proximal short arm of the X chromosome (Fig. 1).
The first descriptions of genetic mapping for CSNBX
suggested close linkage with the locus DXS7, and no
evidence for genetic heterogeneity, 8 " 10 similar to the
first reports of X-linked retinitis pigmentosa
(XLRP). 1112 CSNBX displays phenotypic heterogeneity, with complete and incomplete forms defined by
Investigative Ophthalmology & Visual Science, December 1997, Vol. 3, No. 13
Copyright © Association for Research in Vision and Ophthalmology
Locus for CSNBX Between the RP2 and RP3 Loci
the presence of slight rod function in the latter. Complete CSNBX (CSNB1) was mapped proximal to
DXS7, and this locus was further refined by genetic
analysis in families, without further clinical definition,
to between the loci MAOA and DXS426 (Xpll.3 to
Xpll.23). l8 ' M The map position of this disease indicates potential allelism with one form of XLRP
(JilJ2).lr' Subsequently, a family clinically defined as
incomplete CSNBX (CSNB2) was described with a key
recombination placing the disease proximal to
MAOB,n> consistent with the interval assignment for
CSNB1 and also potentially allelic with RP2 (Fig. 1).
Intrafamilial phenotypic heterogeneity became
apparent when Pearce et al described patients with
complete and incomplete forms of the disease within
the same pedigree.17 The report of disease in a family
with CSNB1 mapping proximal to TIMP-1 (Xpll.23) 18
suggested genetic heterogeneity, in that this genetically defined interval overlaps the previously defined
CSNBX locus only by approximately 100 kb.19 More
recently, evaluation of a single family places CSNBX
between the markers OTC and DXS1003,20 a location
that significantly overlaps the newly defined RP2 critical interval.Ir> Genetic heterogeneity was clearly established when the locus for CSNBX described in a clinically heterogeneous family placed the disease in
Xp21.1.21 This interval is clearly distinct from other
reported locations, bounded by the loci STR44 and
DXS228, and is closely linked to the RP3 gene region,
providing further evidence for a functional relationship between CSNBX and XLRP.
ptcr
— DXS1229
— DXS989
RP15
— DXS1048
~~|
Rl'6
_.
—STK44
—DXSU10
— RPGR - *
RP3
CSNBXa
—OTC
— I3XS1058
— I5XS556
__
—i
2751
In this study, we report a new location on proximal Xp for CSNBX (CSNB4), in a single large family,
which is not associated with previously described
XLRP loci.
PATIENTS AND METHODS
Clinical Assessment
A diagnosis of CSNBX was based on detailed family
history and comprehensive ophthalmic testing at
Moorfields Eye Hospital, London, United Kingdom.
Only men were affected. The phenotype was typical
of the disorder with life-long symptoms of night blindness, reduction of central vision to between 6/12 and
6/36 and high degree of myopia. The electroretinogram (ERG) showed a negative potential without oscillatory potentials to bright white light and was small
to dim blue light (Schubert-Bornschein-type ERG).
Dark adaptation showed little evidence of a rod-cone
break but spectral sensitivity testing demonstrated that
rods mediated vision at short wavelength in the darkadapted state. Thus, the detectable rod function was
such that the condition would be classified as incomplete.
DNA Analysis
All investigations followed the tenets of the Declaration of Helsinki, and informed consent and full institutional review board approval were obtained. The forward primer for each microsatellite was end-labeled
with 32P-ydATP at 37°C for 45 minutes with T4 polynucleotide kinase (New England Biolabs, Hertfordshire, UK). Polymerase chain reaction (PCR) was performed as previously described.22 Alleles were detected by electrophoresing the PCR products on 6%
denaturing polyacrylamide gels (Promega, Southhampton, UK). Details of primer sequences and PCR
conditions for all microsatellites used in this study are
available from Genome Database.
COD1
— DXS993
— DXS1201
— I3XS228
Linkage Analysis
_
_
CSNBXb
Two-point linkage analysis for CSNBX and seven
markers on proximal Xp was carried out with LINKAGE
version 5.1 using MLINK (Columbia University,
Primary
Retinal
New York, NY). The frequency of the CSNBX gene in
Dysplas
— DXS1003
CSNB2
AIED
the general population was taken to be 0.0001. Penetrance values for carriers were set at 0.0000. Alleles at
—TIMP1/I3XS426
_
— IDXS6616
_
marker loci were assumed to have equal frequency,
1 CSNB1
and alteration of frequencies did not affect significant
— DXS225
1
results. ILINK was used to calculate 0 inax and Z,nax.
5
m
Multipoint
linkage analysis (LINKMAP) with loci orFIGURE l. Map of eye diseases on proximal Xp RP15* RP6,
1
1 21
b 20
13 1
der
DXS556-DXS993-DXS1201
was performed, usKP3: CSNBX / COD1™ CSNBX , CSNBX/CNSB1, "
distances of 1 cM and 2 cM, respecCSNB2,"' AIED™ Rl>2,i5 CSNB1,18 primary retinal dyspla- ing genetic
tively.22'23
sia/7 Norrie disease,38 and exudative vitreoretinopathy.39
— DXS7
— MAOA/MAOB Nome 31sca.se
""
— NDI' -4
and Ex udative
Vitr< or ctinnpathy
— DXS8080
-'
CSNBX/CSNB1
— DXS8083
—
Rl>2
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2752
Investigative Ophthalmology & Visual Science, December 1997, Vol. 38, No. 13
pter
,4
3
3
2
4
5
3
1
1
1
2
1
3
2
2
3
2
2
3
1
2
3
4
4
2
1
1
1
1
2
2
3
1
1
Y
wr
III-3
IV-4
IV-3
IV-5
3T1
V-5
V-6
<•)
2 .
_
3 •
1 .
_
2
3 •
4 •
2
1
1
1
!
.
.
•
2 •
3 '
1 '
1 '
—2
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4
—3
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_
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-
-4
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.2
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3
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43
1 •
2
q.3
5
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3
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n.
"+2
2
VI-1
VI-2
FIGURE 2. Pedigree of CSNBX family showing haplotypes constructed with 17 microsatellites
on proximal Xp, localizing disease to between markers DXS556 and DXS8080. Diseaseassociated haplotypes are shown as dark bars, and the hatched bar represents markers that
were uninformative. One woman of unknown clinical status is included in the pedigree (?),
and recombination events are highlighted (*).
RESULTS
Haplotype Analysis
The family was analyzed with 17 polymorphic microsatellite marker loci on proximal Xp, spanning previously identified CSNBX and XLRP loci to create the
haplotypes shown in Figure 2. Subject IV-2, an obligate
carrier, is recombinant, relative to subjects IV-3, IV-4,
and IV-5. This informative recombination locates the
disease-associated haplotype proximal to DXS1110.
The same crossover is observed in subject V-l, indicating that the recombination observed in IV-2 occurred
in generation II of this branch of the family.
The distal boundary of CSNBX in this family is
further refined by a recombination event in subject
V-7, an unaffected man who has inherited the diseaseassociated haplotype at DXS556, placing the disease
proximal to this locus. Subject V-7 does not have night
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blindness; his clinical status was reconfirmed recently
at Moorfields.
Subject V-3 is recombinant, relative to his carrier
mother (IV-2), between the loci DXS8080 and
DXS1201 (MAOB and DXS7 are uninformative), with
the disease-associated haplotype located distal to
DXS8080. The data shown indicate that V-5, a woman
of unknown clinical status, is evidently a carrier of
CSNBX.
In summary, haplotype data clearly define a locus
for CSNBX (CSNB4) between the loci DXS556 and
DXS8080 on Xpll.4 to Xpll.3. Haplotypes also demonstrate that DXS1201 and DXS993 cosegregate with
disease.
Linkage Analysis
Table 1 describes two-point lod scores between CSNB4
and key marker loci on proximal Xp. The informative
Locus for CSNBX Between the RP2 and RP3 Loci
TABLE
2753
l. Two-Point Linkage Analysis Between CSNB4 and Informative Xp Marker Loci
LOD Score at Recombination Fraction of
Locus
0.00
DXS1242
DXS1110
DXS556
DXS993
DXS1201
DXS8080
DXS1003
— 00
— 00
— 00
2.51
1.25
— 00
— 00
0.01
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
-2.06
0.36
0.93
2.47
1.25
-0.54
-0.46
-0.67
0.91
1.46
2.29
1.21
0.08
0.21
-0.12
1.02
1.54
2.06
1.14
0.28
0.43
0.14
1.00
1.49
1.81
1.05
0.35
0.50
0.28
0.92
1.37
1.56
0.95
0.36
0.49
0.35
0.80
1.21
1.31
0.82
0.34
0.44
0.36
0.66
1.02
1.04
0.68
0.30
0.37
0.32
0.50
0.80
0.77
0.53
0.25
0.28
0.25
0.33
0.56
0.51
0.37
0.18
0.18
loci chosen represent regions around CSNBXRP3 (DXS1242,DXS1110), CSNBX-/?P2 (DXS8080,
DXS1003) and loci in the interval between these
regions (DXS556,DXS993,DXS1201). The locus
DXS1003, which lies within the RP2-CSNBX interval
on Xpll.23 1 5 is not linked to CSNB4 (Z, mx = 0.50;
©max = 0.17). Instead, a significant lod score was obtained with DXS993 (Z»nilx = 2.51; 0 m a x = 0). DXS1110
showed considerably weaker linkage to CSNB4 (Z,,,^
= 1.03; 6 m a x = 0.11).
Multipoint analysis was performed to determine
the most likely location of CSNB4 in relation to
DXS556, DXS993, and DXS1201. A maximum lod of
3.2 was scored for the locus order DXS556-1 c M (CSM34-DXS993)-2 cM-DXS1201. A one-lod confidence interval based on these data places the CSNB4
locus in the 24-cM interval proximal to DXS556.
DISCUSSION
CSNBX is know to be phenotypically and genetically
heterogeneous, with three locations for the disease
on proximal Xp. The most commonly reported locus
seems to lie between MAOA and DXS426,13'14 overlapping other locations,16'20 and is consistent with the
newly defined locus assignment for RP2.15 Bech-Hansen et al described another location proximal to
TIMP-1,18 and a third locus for CSNBX linked to the
RP3 gene region was reported by Bergen et al. 2i Aland
Islands eye disease (AIED), a clinically variant form of
CSNBX, has a genetic interval defined by the loci
DXS7 and DXS255,24'25'26 which is compatible with the
most commonly reported locus assignment for
CSNBX.
Haplotype analysis in this study using 17 microsatellites on proximal Xp has revealed a new location
for CSNBX (CSNB4) between the loci DXS556 and
DXS8080. The genetic interval is estimated to be 5 to
6 cM,22'23 and is not associated with localizations for
7
'•'max
0.36
1.03
1.54
2.51
1.25
0.36
0.50
0mnv
0.29
0.11
0.96
0.00
0.00
0.19
0.17
DXS1110, suggests the order DMD-DYSl-(DXS1110CSNBX-XLRP3)-DXS7-DXS1003, which is indicative
of potential allelism with RP3. Another group has since
reported a mutation in the RP3 gene {RPGR) causing
CSNBX, confirming allelism.29 In contrast, multipoint
linkage analysis in this study suggests the order DXS5561 cM-(CS7VB4-DXS993)-2 cM-DXS1201 with a maximum lod score of 3.2.
These data, coupled with informative recombinations in the family described here, clearly distinguishes
this disease from RP3, RP2, and their associated
CSNBX loci.
CSNB4 appears to map to the same interval as Xlinked cone-rod dystrophy (CODI).3031 COD/was subsequently refined to an interval bounded by the loci
DXS1058 and DXS1201 in X p l l . 4 to Xpll.3, 3 2 with
DXS993 showing no crossovers. It should also be
noted that DXS993 cosegregates fully without recombination with CSNB4, therefore raising the possibility
that CODI and CSNB4 could be allelic variants. Because mutations in Peripherin-RDS can cause c o n e rod dystrophy or RP, and as already discussed, mutations in RHO, PDEfi, and RPGR can cause CSNB and
RP, it seems reasonable to assume that further studies
of families with XLRP may reveal a potentially allelic
locus with this newly defined 5- to 6-cM interval.
It is particularly interesting to observe that many
families with XLRP appear to segregate with the RP3
locus (that is, disease is distal to DXS7 and proximal
to other XLRP loci), which is reportedly more common than RP2.3S However, relatively few mutations
in the RPGR gene have been discovered to date. 2734
Because it is possible that another gene more proximal to RPGR is causing disease in these families, the
potential for this new common interval for various
forms of retinal dystrophy (CSNB4 and CODI) also
segregating with an as yet undefined XLRP locus can
not be excluded.
RP327 or RP2.15
Key Words
The genetic interval for CSNBX described by Bergen et al,21 combined with new data from a different
family28 that show no recombination with the locus
allelic, haplotype analysis, heterogeneity, stationary night
blindness, X-linked congenital, X-linked retinitis pigmen tosa
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2754
Investigative Ophthalmology & Visual Science, December 1997, Vol. 38, No. 13
Acknowledgments
The authors thank the Human Genome Mapping Project
(HGMP) Resource Centre for oligonucleotide provision and
Dr. Arthur Bergen, Dr. Chris Inglehearn, and Neil Ebenezer
for their advice during preparation of this manuscript.
15.
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