Linkage analysis in X-linked congenital stationary night blindness

GENOMICS14, 99-104 (1992)

Linkage Analysis in X-Linked Congenital Stationary Night Blindness M. A. ALDRED,* K. L. DRY,* D. M. SHARP,'I" D. B. VAN DORP,:I: J. BROWN,* L. J. HARDWlCK,* D. H. LESTER,* F. E. PRYDE,* P. W. TEAGUE,* M. JAY,'I" A. C. BIRD,t B. JAY,'I" AND A. F. WRIGHT* *MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom; $Oepartment of Clinical Ophthalmology, University of London, Moorfields Eye Hospital, City Road, London, United Kingdom; and SDepartments of Clinical Genetics and Ophthalmology, Free University, Amsterdam, The Netherlands

ReceivedDecember29, 1991;revisedMay4, 1992 X L - C S N B is a single clinical e n t i t y m a n i f e s t i n g a wide v a r i a t i o n in clinical expression. It is not yet clear w h e t h e r the observed v a r i a t i o n in clinical expression of X L - C S N B r e p r e s e n t s u n d e r l y i n g genetic heterogeneity. L i n k a g e studies to date h a v e involved m a i n l y c o m p l e t e X L - C S N B families ( M u s a r e l l a et al., 1989) or have not distinguished b e t w e e n the suggested clinical subgroups (Gal et al., 1989). T h e family studied b y B e c h - H a n s e n et al. (1990) was one of t h o s e r e p o r t e d b y P e a r c e et al. (1990) to c o n t a i n p a t i e n t s w i t h b o t h the c o m p l e t e a n d the i n c o m p l e t e t y p e s of C S N B . A l l t h r e e groups r e p o r t e d linkage to the s h o r t a r m of the X c h r o m o s o m e . N o r e c o m b i n a t i o n was f o u n d b e t w e e n C S N B a n d D X S 7 in the t h r e e studies, while m a x i m u m lod scores with D X S 2 5 5 were f o u n d at r e c o m b i n a t i o n fractions of 6% ( B e c h - H a n s e n et al., 1990), 14% (Gal et al., 1989), a n d 17% ( M u s a r e l l a et al., 1989). Analysis of m u l t i p l y i n f o r m a t i v e crossovers b y M u s a r e l l a et al., (1989) showed t h a t c o m p l e t e X L - C S N B ( C S N B 1 ) is m o s t p r o b a b l y located b e t w e e n O T C a n d T I M P , b u t its location relative to D X S 7 has not b e e n established. M u sarella et al., (1989) also studied one family with " i n c o m p l e t e " X L - C S N B , described previously b y K h o u r i et al. (1988) as being of m i x e d c o m p l e t e / i n c o m p l e t e type, b u t f o u n d no evidence to s u p p o r t the h y p o t h e s i s of genetic heterogeneity. W e have u n d e r t a k e n a genetic linkage s t u d y of t h r e e X L - C S N B families to a t t e m p t to establish the location of this gene relative to six X p m a r k e r s .

X - l i n k e d c o n g e n i t a l s t a t i o n a r y n i g h t b l i n d n e s s (XLC S N B ) is a n o n p r o g r e s s i v e d i s o r d e r o f t h e r e t i n a , c h a r acterized by night blindness, reduced visual acuity, and myopia. Previous studies have localized the CSNB1 l o c u s to t h e r e g i o n b e t w e e n O T C a n d T I M P o n t h e s h o r t arm of the X chromosome. We have carried out linkage studies in three XL-CSNB families that could not be c l a s s i f i e d a s e i t h e r c o m p l e t e or i n c o m p l e t e C S N B o n t h e c r i t e r i a s u g g e s t e d b y M i y a k e e t al. ( 1 9 8 6 . A r c h . O p h thalmol. 104: 1013-1020). We used markers for the DXS538, DMD, OTC, MAOA, DXS426, and TIMP loci. T w o - p o i n t a n a l y s e s s h o w t h a t t h e r e is c l o s e l i n k a g e b e t w e e n C S N B a n d M A O A (0m~ = 0 . 0 5 , Zmax = 3 . 3 9 ) , D X S 4 2 6 (0m~ = 0 . 0 6 , Zmax = 2 . 4 2 ) , a n d T I M P (0m~ = 0.07, Z~ = 2.04). Two multiply informative crosso v e r s a r e c o n s i s t e n t w i t h C S N B l y i n g p r o x i m a l to M A O A a n d d i s t a l to D X S 4 2 6 , r e s p e c t i v e l y . M u l t i p o i n t analysis supports this localization, giving the most likely order as DMD-17 cM-MAOA-7.5 cM-CSNB7.5 cM-DXS426/TIMP-cen, and thus refines the locali z a t i o n o f C S N B . © 1 9 9 2 A c a d e m i c Press, Inc.

INTRODUCTION X - l i n k e d congenital s t a t i o n a r y n i g h t blindness ( X L C S N B ) is a n o n p r o g r e s s i v e disorder of t h e retina, characterized b y n i g h t blindness, myopia, n y s t a g m u s , a n d reduced visual acuity. D a r k a d a p t a t i o n tests show reduced or a b s e n t rod a d a p t a t i o n . T h e e l e c t r o r e t i n o g r a m ( E R G ) of affected m a l e s is a b n o r m a l , with an a b s e n t or severely reduced scotopic b-wave. Carrier s t a t u s in fem a l e s is n o t generally detectable b y clinical m e a n s . M i y a k e et al. (1986) h a v e classified C S N B of m i x e d genetic t y p e s into two clinical subgroups, t e r m e d c o m p l e t e a n d i n c o m p l e t e C S N B , on the basis of refractive error, E R G , a n d d a r k a d a p t a t i o n responses. C o m p l e t e a n d inc o m p l e t e C S N B did n o t coexist in a n y of t h e families in t h a t study. However, others have f o u n d e x a m p l e s of b o t h c o m p l e t e a n d i n c o m p l e t e C S N B p a t i e n t s within the s a m e X - l i n k e d pedigrees ( K h o u r i et al., 1988; P e a r c e et al., 1990). T h i s led P e a r c e et al. (1990) to p r o p o s e t h a t

MATERIALS AND METHODS Patients and families. Patients were ascertained through the Genetic Clinic, Moorfields Eye Hospital, London (families 3 and 4), and through the clinic of Dr. D. B. van Dorp, Amsterdam (family 2). All affected individuals in family 2 showed the features typical of complete CSNB, except for individual III-2, who is hyperopic, but had no b-wave on electroretinography, impaired dark adaptation, nyctalopia, nystagmus, and impaired visual acuity. In families 3 and 4 the patients showed the features typical of Xlinked CSNB, with a life-long history of visual difficulties, high myopia, and reduced visual acuity. Electrophysiological testing showed no recordable rod function to a dim blue light stimulus. However, a rodcone break was recorded on dark adaptation and rods mediated detection of light at short wavelengths (Sharp et al., 1990). The detection of

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ALDRED E T AL.

TABLE 1 M a r k e r s U s e d in L i n k a g e A n a l y s i s w i t h X L - C S N B Locus

Location

Polymorphism

PIC a

Reference

DXS538 DMD,AC1 DMD,AC2 OTC MAOA DXS426 TIMP

Xp21.1-p11.21 Xp21.1 Xp21.1 Xp21.1 Xpll.3 Xp21.1-p11.23 Xpll.3-p11.23

AC repeat AC repeat AC repeat DraI AC repeat AC repeat BglII/BglI

0.72 0.79 0.82 0.44 0.69 0.52 0.68

Browne et al. (1991) Feener et al. (1991) Feener et al. (1991) Petty et al. (1991) Black et al. (1991) Coleman et al. (1990); Luty et al. (1990) Aldred and Wright (1991)

a

Theoretical PIC or observed heterozygosity, as detailed in the reference.

rod function by psychophysical means shows the disorder to be different from the complete form as described by Miyake et al. (1986), despite the high myopia and the unrecordable rod response on ERG. D N A analysis. DNA was extracted from EDTA-anticoagulated frozen blood, using an Applied Biosystems DNA extractor. The DNA was analyzed using eight polymorphisms at six loci, all detectable by polymerase chain reaction (PCR). The polymorphisms examined are listed in Table 1. DMD*AC1 and DMD*AC2 are AC-repeat polymorphisms near the "brain" promoter at the 5' end of the dystrophin gene (Feener et al., 1991). PCR primers and conditions for detecting each polymorphism were as detailed in the relevant reference. AC-repeat polymorphisms were run on 16-cm-long, 1.5-ram-thick denaturing polyacrylamide gels, containing 42% urea. The acrylamide concentration was 7.5% for DXS426, 8% for DXS538, DMD*AC1, and DMD.AC2, and 15% for MAOA. Alleles were visualized by silver staining, using the Bio-Rad silver stain kit according to the manufacturer's instructions. Linkage analysis. Linkage analyses were carried out using the LINKAGE version 5.03 program package (MLINK for two-point analyses and L I N K M A P for multipoint). The order of the loci was assumed to be t e l - D M D - O T C - M A O A - D X S 4 2 6 - T I M P (Mandel et al., 1989; Coleman et al., 1991). Genetic distances used were D M D MAOA 17 cM and M A O A - D X S 4 2 6 / T I M P 15 cM (Ott et al., 1990; Mahtani et al., 1991). DXS538 has been localized between DXS164 and DXS7 (Browne et aI., 1991), but its position relative to the DMD polymorphisms was not known prior to this study. T I M P and DMD each had two polymorphisms t h a t were combined into haplotypes and treated as single loci. To maximize use of the data in the multipoint analysis, results for DXS426 and T I M P were further combined and treated as a single locus. This is necessary because the size of the arrays in the program is limited, and it is not possible to run

a five-point analysis with DXS426 and T I M P as separate loci. The combining of the data is justified on the basis t h a t the loci are closely linked physically (Coleman et al., 1991) and do not recombine with each other in the three families studied here.

RESULTS Two-Point

Linkage

Analysis

Table 2 shows the two-point lod scores between probes, and Table 3 shows pairwise scores between CSNB and the marker loci. The OTC DraI polymorphism was uninformative in these families and therefore t h e r e s u l t s a r e n o t s h o w n . N o r e c o m b i n a t i o n is s e e n b e tween TIMP and DXS426, allowing these data to be combined for the multipoint analysis. CSNB recomb i n e s a t l e a s t o n c e w i t h e a c h o f t h e m a r k e r l o c i . I t is m o s t closely linked to MAOA (0ma~ = 0 . 0 5 , Zma~ = 3 . 3 9 ) , D X S 4 2 6 (0max = 0 . 0 6 , Zma x = 2 . 4 2 ) , a n d T I M P (0~ax = 0.07, Zmax = 2 . 0 4 ) . The families and probe results are displayed in Figs. 1 - 3 . F a m i l y 2 ( F i g . 1) is i n f o r m a t i v e f o r t h e f o u r l o c i shown (DXS538 was not examined) and shows no recomb i n a t i o n . I n f a m i l y 3 ( F i g . 2), r e c o m b i n a t i o n between DMD and CSNB in individual V-10 places XL-CSNB p r o x i m a l t o D M D . T h i s is s u p p o r t e d b y t h r e e r e c o m b i n a n t s i n f a m i l y 4 ( F i g . 3), i n d i v i d u a l s V I - 1 , V I - 9 , a n d

TABLE 2 Pairwise LOD Scores between Probes

Loci

0.00

0.01

0.05

0.10

0.20

0.30

0.40

0ma~

Zma~

DXS538-DMD DXS538-MAOA DXS538-DXS426 DXS538-TIMP DMD-MAOA DMD-DXS426 DMD-TIMP MAOA-DXS426 MAOA-TIMP DXS%26-TIMP

- ~ -oo -06 - ~ -05 -oo -oo 1.75 2.07 3.36

2.09 -2.72 -0.34 -0.83 -4.14 0.33 1.38 1.75 2.04 3.30

2.51 -1.12 0.35 -0.07 -1.55 0.99 1.94 1.70 1.90 3.03

2.45 -0.41 0.59 0.24 -0.47 1.18 2.02 1.58 1.71 2.67

2.00 0.16 0.66 0.43 0.32 1.12 1.77 1.20 1.29 1.90

1.38 0.28 0.51 0.39 0.47 0.80 1.29 0.74 0.85 1.13

0.70 0.19 0.27 0.22 0.32 0.37 0.69 0.30 0.42 0.44

0.06 0.30 0.17 0.22 0.29 0.13 0.09 0.00 0.00 0.00

2.52 0.28 0.67 0.43 0.47 1.20 2.02 1.75 2.07 3.36

:

LINKAGE ANALYSIS 1N XL-CSNB

i01

TABLE 3

Two-Point Lod Scores between CSNB and Marker Loci

0.00

0.01

0.05

0.10

DXS538 Family 3 Family 4 Total

-2.30 -oo -oo

0.45 -1.72 -1.27

1.01 -0.44 0.57

1.12 0.02 1.14

DMD Family 2 Family 3 Family 4 Total

1.03 -oo -oo -oo

1.01 -2.21 -4.81 -6.01

0.94 -0.81 -2.16 -2.03

MAOA Family 2 Family 3 Family 4 Total

1.03 1.90 -oo -oo

1.01 1.86 0.19 3.06

DXS426 Family 2 Family 3 Family 4 Total

1.03 1.43 oo -~

TIMP Family 2 Family 3 Family 4 Total

1.03 1.16 -oo -~

0.30

0.40

0m~

Zm~x

1.05 0.30 1.35

0.80 0.32 1.12

0.45 0.20 0.65

0.18

1.35

0.85 -0.26 -1.13 -0.54

0.64 0.15 -0.29 0.50

0.42 0.24 0.01 0.67

0.18 0.17 0.09 0.44

0.28

0.68

0.94 1.72 0.73 3.39

0.85 1.54 0.83 3.22

0.64 1.17 0.72 2.53

0.42 0.78 0.47 1.67

0.18 0.38 0.20 0.76

0.05

3.39

1.01 1.41 -0.42 2.00

0.92 1.30 0.19 2.41

0.80 1.18 0.36 2.34

0.57 0.89 0.41 1.87

0.32 0.60 0.32 1.24

0.10 0.30 0.18 0.58

0.06

2.42

1.01 1.14 -0.60 1.55

0.94 1.06 0.01 2.01

0.85 0.96 0.20 2.01

0.64 0.74 0.29 1.67

0.42 0.51 0.24 1.17

0.18 0.27 0.14 0.59

0.07

2.04

V I I - 5 . T h e s e r e c o m b i n a n t s are also i n f o r m a t i v e for D X S 5 3 8 a n d p l a c e C S N B p r o x i m a l to t h i s locus. T h e s i m p l e s t e x p l a n a t i o n for t h e r e s u l t s i n i n d i v i d u a l s VI-11, VI-12, a n d V L 1 3 of f a m i l y 4 is t h e h a p l o t y p e a r r a n g e m e n t s h o w n i n Fig. 3. V I - 1 1 is r e c o m b i n a n t w i t h T I M P and DXS426 but not with MAOA, placing CSNB distal to D X S 4 2 6 a n d T I M P . H i s b r o t h e r , VI-12, is r e c o m b i nant with MAOA but not DXS426 and TIMP, indicati n g t h a t t h e g e n e is p r o x i m a l to M A O A .

0.20

p o l y m o r p h i s m s . A t h r e e - p o i n t a n a l y s i s of D X S 5 3 8 against D M D a n d M A O A confirms t h a t the most likely o r d e r is D X S 5 3 8 - D M D - M A O A , b u t t h i s is o n l y 1.7 times more likely t h a n D X S 5 3 8 placed b e t w e e n D M D

I

CSNB2 DMD MAOA DXS426 TIMP

2 1 I 3

2 2 1

I

I

I(1) 11(2) 1(2)

Multipoint Linkage Analysis A f o u r - p o i n t a n a l y s i s w a s c a r r i e d o u t to d e t e r m i n e t h e l o c a t i o n of C S N B i n r e l a t i o n to D M D , M A O A , a n d D X S 4 2 6 / T I M P . T h e r e s u l t s are s h o w n i n T a b l e 4 a n d Fig. 4. T h e m o s t l i k e l y o r d e r w a s D M D - M A O A - X L CSNB-DXS426/TIMP. T h i s o r d e r is 4.8 t i m e s m o r e l i k e l y t h a n C S N B b e t w e e n D M D a n d M A O A a n d 7.8 t i m e s m o r e l i k e l y t h a n C S N B p r o x i m a l to D X S 4 2 6 / TIMP.

Location of DXS538 Recombination has occurred between DXS538 and D M D i n i n d i v i d u a l V - 4 of f a m i l y 4 (Fig. 3). I f D X S 5 3 8 were p r o x i m a l to D M D , t h e n a n o t h e r r e c o m b i n a t i o n e v e n t w o u l d b e r e q u i r e d b e t w e e n D X S 5 3 8 a n d MAOA.. I t t h e r e f o r e s e e m s l i k e l y t h a t D X S 5 3 8 is d i s t a l to t h e D M D

II DMD MAOA DXS426 TIMP

1 2

III DMD MA©A DXS426 TIMP

2 1 3

2 1

I

1 2 2

2 1 2

1 2 1

2 1 a

FIG. 1. Segregation of alleles in family 2. The affected haplotype is shown as a thick solid line. Alleles in parentheses have been inferred. Females are classified as obligate carriers if they have an affected father or son; otherwise they are classified as status unknown. There are no recombinants in this family. The affected chromosome is apparently inherited from the grandfather I-2, whose clinical status is unknown.

IV DXS536 DMD MAOA DXS426 TIMP

2 4 2 1 2

DXS538 DMD MAOA DXS42.5 TlMP

57 DXS538 DMD MAOA DXS426 TIMP

3 5 2 2 I 1

DXS538 DMD MAOA DXS426 TIMP

DXS538 DMD MAOA DXS426 TlMP

2 2 1 2 I 1

VI DXS538 EMD MAOA DXS426 TIMP

FIG. 2. lying

proximal

Family 3 shows recombination to these markers. There

between DXS538/DMD is no recombination between

and CSNB in individuals the disease and more

IV-3 and V-10, proximal markers.

consistent (Symbols

with the disease used as in Fig.

locus 1.)

I

II

CSNB 4

III

IV

II 3421

12

TIMP DXS426 DMD DXS538 MAOA

VII DXS538 DMD MAOA DXS426 TIMP

2 2 1 2 1

I I1 1 2 2 1

2 2 2 1

FIG. 3. Family 4 supports the localization of CSNB proximal to DMD (e.g., VI-l, VI-g, VII-5). In individual VI-13, we do not know which allele of MAOA is inherited from the mother and which is the paternal allele. However, the simplest haplotype arrangement (i.e., minimizing the number of recombinants) is that shown. This suggests that CSNB is distal to DXS426 and TIMP (VI-11) and proximal to MAOA (VI-12). DXS538 is shown distal to DMD to avoid a double recombinant in V-4. (Symbols used as in Fig. 1.)

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L I N K A G E ANALYSIS IN XL-CSNB

and MAOA. We have also found t h a t DXS538 is deleted in DNA from the patient BB (Francke et al., 1985).

LOD 4

DISCUSSION

3-

The CSNB1 locus has been localized to the short arm of the X chromosome by linkage analysis (Gal et al., 1989; Musarella et al., 1989; Bech-Hansen et al., 1990). The three families studied in this paper show traits typical of X-linked congenital stationary night blindness, but do not fulfill all the requirements of Miyake et al. (1986) for the complete type of CSNB (CSNB1). However, neither do they fulfill all the criteria of incomplete CSNB as described by these authors. Our linkage data give results similar to those published previously on CSNB1 families, with tight linkage to MAOA ( 0 m a x = 0.05, Zmax = 3.39) and DXS426 (0max = 0.06, Z ~ = 2.42). Further refinement of the previous assignment is dependent on the demonstration of multiply informative crossovers. Musarella et al. (1989) reported several such events that were consistent with a localization for CSNB1 proximal to OTC and distal to TIMP. However, none of these recombinants was informative with D XS7. We have identified two multiply informative crossovers with CSNB. One is recombinant with DXS538, DMD, and MAOA, but not with DXS426 and TIMP. This is consistent with the CSNB locus in these families lying proximal to MAOA. Since MAOA is thought to be close to DXS7 (<600 kb) on the basis of physical mapping data, this result implies that the disease locus is also likely to be proximal to DXS7. The second crossover event was recombinant with T I M P and DXS426, but nonrecombinant with DXS538, DMD, and MAOA. This is consistent with the XL-CSNB locus lying distal to TIMP, as proposed for CSNB1 by Musarella et al. (1989). Multipoint analysis showed the most likely order to be DMD-17 cM-MAOA-7.5 cM-CSNB-7.5 cMDXS426/TIMP, with a maximum lod score of 3.74. This is consistent with our haplotype analysis. We have also found that DXS538 is slightly more likely to map distal, rather than proximal, to the dystrophin "brain" promoter polymorphisms. DXS538 has previously been localized between DXS164 and DXS7 (Browne et al., 1991). In conclusion, our studies on three families with Xlinked congenital stationary night blindness indicate that the CSNB gene is localized between MAOA and

2

TABLE

4

Results of Four-Point Locus order A: B: C: D:

CSNB-DMD-MAOA-DXS426/TIMP DMD-CSNB-MAOA-DXS426/TIMP DMD-MAOA-CSNB-DXS426/TIMP DMD-MAOA-DXS426/TIMP-CSNB

Analysis Zm~x 0.89 3.06 3.74 2.85

Relative orders C C C B

v v v v

A B D D

Odds 708:1 4.8:1 7.8:1 1.6:1

1 0 -1 -2

•-3

I -60

L -40

,MAOA p/DXS426/TIMP 20

-20

I 40

I 60

cM F I G . 4. Results of the multipoint analysis of CSNB against DMD, MAOA, and DXS426/TIMP. MAOA was arbitrarily assigned at 0 cM, with D X S 4 2 6 / T I M P at +15 cM and DMD at - 1 7 cM. The highest lod score (3.74) is obtained with XL-CSNB equidistant between MAOA and DXS426/TIMP.

DXS426 on the short arm of the X chromosome. The recent localization of CSNB1 proximal to DXS7 (BechHansen et al., 1992) is in agreement with our data. It is interesting to note that Musarella et al. (1989) were unable to distinguish between the orders CSNB1D X S 7 - T I M P and D X S 7 - C S N B 1 - T I M P with seven complete CSNB pedigrees, but when their "incomplete" CSNB family was added, the latter order was 9863 times more likely. In combination with our results, this suggests that X-linked congenital stationary night blindness may not be genetically heterogeneous. ACKNOWLEDGMENTS We acknowledge the generous financial support of the British Retinitis Pigmentosa Society, the National Retinitis Pigmentosa Foundation, and George Gund Foundation. We also t h a n k Norman Davidson for the art work. REFERENCES Aldred, M. A., and Wright, A. F. (1991). PCR detection of existing and new polymorphism at the T I M P locus. Nucleic Acids Res. 19: 1165. Bech-Hansen, N. T., Field, L. L., Schramm, A. M., Reedyk, M., Craig, I. W., Fraser, N. J., and Pearce, W. G. (1990). A locus for X-linked congenital stationary night blindness is located on the proximal portion of the short arm of the X chromosome. Hum. Genet. 8 4 : 406-408. Bech-Hansen, N. T., Moore, B. J., and Pearce, W. G. (1992). Mapping of locus for X-linked congenital stationary night blindness (CSNB1) proximal to DXS7. Genornics 12: 409-411. Black, G. C. M., Chen, Z.-Y., Craig, I. W., and Powell, J. F., (1991). Dinucleotide repeat polymorphism at the MAOA locus. Nucleic Acids Res. 19: 689. Browne, D. L., Luty, J. A., and Litt, M. (1991). Dinucleotide repeat polymorphism at the DXS538 locus. Nucleic Acids Res. 19: 1161. Coleman, M., Bhattacharya, S., Lindsay, S., Wright, A. F., Jay, M., Litt, M., Craig, I. W., and Davies, K. E. (1990). Localization of the

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microsatellite probe DXS426 between DXS7 and DXS255 on Xp and linkage to X-linked retinitis pigmentosa. Am. J. Hum. Genet. 47: 935-940. Coleman, M. P., Murray, J. C., Willard, H. F., Nolan, K. F., Reid, K. B. M., Blake, D. J., Lindsay, S., Bhattacharya, S. S., Wright, A.F., and Davies, K. E. (1991). Genetic and physical mapping around the Properdin P gene. Genomics 11: 991-996. Feener, C. A., Boyce, F. M., and Kunkel, L. M. (1991). Rapid detection of CA polymorphisms in cloned DNA: Application to the 5' region of the dystrophin gene. Am. J. Hum. Genet. 48: 621-627. Francke, U., Ochs, H. D., De Martinville, B., Giacalone, J., Lindgren, V., Dist~che, C., Pagon, R. A., Hofker, M. H., Van Ommen, G.-J. B., Pearson, P. L., and Wedgwood, R. J. (1985). Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa and McLeod syndrome. Am. J. Hum. Genet. 37: 250-267. Gal, A., Schinzel, A., Orth, U., Fraser, N~ A., Mollica, F., Craig, I. W., Kruse, T., M~ichler, M., Neugebauer, M., and Bleeker-Wagemakers, L. M. (1989). Gene of X-chromosomal congenital stationary night blindness is closely linked to DXS7 on Xp. Hum. Genet. 81: 315318. Khouri, G., Mets, M. B., Smith, V. C., Wendell, M., and Pass, A. S. (1988). X~linked congenital stationary night blindness: Review and report of a family with hyperopia. Arch. Ophthalmol. 106: 14171422. Luty, J. A., Guo, Z., Willard, H. F., Ledbetter, D. H., Ledbetter, S., and Litt, M. (1990). Five polymorphic microsatellite VNTRs on the human X chromosome. Am. J. Hum. Genet. 46: 776-783. Mahtani, M. M., Lafreni~re, R. G., Kruse, T. A., and Willard, H. F.

(1991). An 18-locus linkage map of the pericentromeric region of the human X-chromosome: Genetic framework for mapping X-linked disorders. Genomics 10: 849-857. Mandel, J.-L., Willard, H. F., Nussbaum, R. L., Romeo, G., Puck, J. M., and Davies, K. E. (1989). Report of the committee on the genetic constitution of the X chromosome. Cytogenet. Cell Genet. 51: 384-437. Miyake, Y., Yagasaki, K., Horiguchi, M., Kawase, Y., and Kanda, T. (1986). Congenital stationary night blindness with negative electroretinogram. Arch. Ophthalmol. 104: 1013-1020. Musarella, M. A., Weleber, R. G., Murphey, W. H., Young, R. S. L., Anson-Cartwright, L., Mets, M., Kraft, S. P., Polemeno, R., Litt, M., and Worton, R. G. (1989). Assignment of the gene for complete X-linked congenital stationary night blindness (CSNB1) to Xp11.3. Genomics 5: 727-737. Ott, J., Bhattacharya, S., Chen, J. D., Denton, M. J., Donald, J., et al. (1990). Localizing multiple X chromosome-linked retinitis pigmentosa loci ~using multilocus homogeneity tests. Proc. Natl. Acad. Sci. USA 8"/: 701-704. Pearce, W. G., Reedyk, M., and Coupland, S. G. (1990). Variable expressivity in X-linked congenital stationary night blindness. Can. J. Ophthalmol. 25: 3-10. Petty, E. M., Carstens, R., and Bale, A. E. (1991). Ornithine transcarbamylase polymorphism detected by PCR introduction of DraI site. Nucleic Acids Res. 19: 690. Sharp, D. M., Arden, G. B., Kemp, C. M., Hogg, C. R., and Bird, A. C. (1990). Mechanisms and sites of loss of scotopic sensitivity: A clinical analysis of congenital stationary night blindness. Clin. Vis. Res. 5: 217-230.