January 2000
Volume 41, Issue 1
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Retina  |   January 2000
Autosomal Dominant Macular Atrophy at 6q14 Excludes CORD7 and MCDR1/PBCRA Loci
Author Affiliations
  • Irina B. Griesinger
    From the W. K. Kellogg Eye Center, University of Michigan, Ann Arbor.
  • Paul A. Sieving
    From the W. K. Kellogg Eye Center, University of Michigan, Ann Arbor.
  • Radha Ayyagari
    From the W. K. Kellogg Eye Center, University of Michigan, Ann Arbor.
Investigative Ophthalmology & Visual Science January 2000, Vol.41, 248-255. doi:
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      Irina B. Griesinger, Paul A. Sieving, Radha Ayyagari; Autosomal Dominant Macular Atrophy at 6q14 Excludes CORD7 and MCDR1/PBCRA Loci. Invest. Ophthalmol. Vis. Sci. 2000;41(1):248-255.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. Localization of the gene responsible for autosomal dominant atrophic macular degeneration (adMD) in a large pedigree UM:H785.

methods. Standard ophthalmologic examinations were performed. Microsatellite markers were used to map the disease gene by linkage and haplotype analyses.

results. The macular degeneration in this family is characterized by progressive retinal pigment epithelial atrophy in the macula without apparent peripheral involvement by ophthalmoscopy or functional studies. Acuity loss progressed with age and generally was worse in the older affected individuals. The rod and cone function remained normal or nearly normal in all tested affected members up to 61 years of age. The phenotype in our family has characteristics similar to Stargardt-like macular degeneration with some differences. Haplotype analysis localized the disease gene in our adMD family to an 8-cM region at 6q14, which is within the 18-cM interval of STGD3 but excludes cone-rod dystrophy 7 (CORD7; centromeric) and North Carolina macular degeneration and progressive bifocal chorioretinal atrophy (MCDR1/PBCRA; telomeric). The mapping interval overlaps with that of recessive retinitis pigmentosa (RP25).

conclusions. These results implicate at least three genetically distinct loci for forms of macular degeneration that lie within a 30-cM interval on chromosome 6p11–6q16: CORD7, adMD, and MCDR1/PBCRA. Because the critical interval for the adMD family studied overlaps with STGD3 and RP25, these loci could be allelic.

Macular degenerations are a heterogeneous group of disorders that affect function of the sensory retina, retinal pigment epithelium (RPE) of the macula, or both and result in reduced visual acuity. More than 30 genetically distinct macular disorders have been described. 1 Color vision is impaired in some forms of macular degeneration, particularly those designated as involving cone degeneration. Mutations in some of these genes cause a broad phenotype spectrum and can also affect peripheral retinal function and thereby mimic retinal degeneration, as occurs with some RDS/peripherin mutations. 2  
We studied a five-generation pedigree (family UM:H785) with atrophic macular degeneration that follows autosomal dominant (ad) inheritance and maps to chromosome 6q14. The condition bears some resemblance to recessive Stargardt disease but without the dark fluorescein angiogram frequently found in that condition. 3 Several other forms of retinal/macular degenerations have been mapped to the pericentromeric region of chromosome 6 including an autosomal dominant condition termed Stargardt-like macular degeneration (Fig. 4) . 4 5 6 7 8 9 10 11 The disease-causing gene locus in our family could be allelic to one or more of those conditions. 
By linkage and haplotype analysis, we excluded the cone-rod dystrophy 7 (CORD7), North Carolina macular degeneration (MCDR1), and progressive bifocal chorioretinal atrophy (PBCRA) loci from the disease gene interval of our adMD family. As a consequence, our data demonstrate that there must be at least three genetically independent loci for forms of macular degeneration within the 30-cM interval on 6p11–6q16. We describe the phenotype of this family and present the genetic interval for this condition. 
Methods
Examinations were performed on 10 affected and 4 unaffected members, 15 to 67 years of age, in pedigree UM:H785 (Fig. 1) , with informed consent in conjunction with molecular genetic analysis. The research followed the tenets of the Declaration of Helsinki. Visual fields were determined by Goldmann perimetry using white targets. Color vision was tested with Ishihara plates and the Farnsworth D-15 color panel. 12 Rod absolute threshold sensitivities were determined at six loci across the horizontal meridian using a Goldmann-Weekers dark adaptometer after 1 hour of dark-adaptation. The Ganzfeld electroretinogram (ERG) was recorded at 0.1 to 1000 Hz (−3 dB) with bipolar contact lens electrodes after full pupillary dilation. Normal values from 50 control subjects 8 to 65 years of age were as follows: scotopic rod b-wave mean = 325 μV (SD = 82, min ≥ 204 μV), elicited by 0.5-Hz dim blue (440-nm peak, 70-nm half-width) stimuli at −1.86 log cd-s/m2; photopic cone b-wave mean = 124 μV (SD = 36, min ≥ 56 μV), elicited by 0.5-Hz “white” flashes (0.62 log cd-s/m2) on a 43-cd/m2 background; and cone 30-Hz flicker response mean = 92 μV (SD = 31, min≥ 52 μV) and implicit times ≤32 msec, for 30-Hz “white” stimuli of 0.62 log cd-s/m2 per flash. 
Genotyping
Blood samples were obtained from 24 family members and 6 spouses, and leukocyte DNA was extracted. Genotyping was performed as described previously. 13 The PCR products were separated by denaturing gel electrophoresis and visualized by autoradiography. Descriptions of the polymorphic markers and genetic distances were obtained from the Genome Database (http://gdb.wehi.edu.au/gdb/gdbtop.html). 
Linkage Analysis
Two point linkage analysis was performed between the disease gene and each marker using the MLINK program (version 5.1) of the LINKAGE package. 14 The disease was coded as a fully penetrant autosomal dominant trait with a gene frequency of 0.00001 for the affected allele. Marker allele frequencies given in the Genome Database were used. 
Results
Clinical Description
Pedigree UM:H785 (Fig. 1) has atrophic macular degeneration that follows autosomal dominant inheritance, with individuals affected in five consecutive generations and male-to-male transmission. Clinical features of 10 affected individuals are summarized in Table 1 . Some individuals were affected by teenage years. Acuity loss progressed with age, and the older affected members generally had worse symptoms. The peripheral retina normally was spared on visual field testing, and full-field ERG function was normal or nearly normal across all ages tested up to 61 years of age. This was not a primary cone dystrophy, as judged by nearly normal color vision and cone ERGs (Fig. 2)
As an example of typical findings of affected individuals in this family, female IV:6 had visual acuities of 20/70 in both eyes at 42 years of age that decreased to 20/200 several years later. However, her color vision remained good throughout this time, with 13 of 14 Ishihara plates identified correctly with either eye. Both maculae showed central atrophy surrounded by yellowish “flecks,” and “window defect” clusters were seen on the fluorescein angiogram (Fig. 3F ). Peripheral retinal function was spared as judged by normal visual fields even with the small I4e Goldmann target, normal full-field rod dark-adapted sensitivities, and normal cone ERG responses except for a slight delay of the 30-Hz flicker implicit time to 34 msec (Fig. 2) . RPE integrity was good as judged by normal electro oculogram (EOG) Arden ratios of 2.2 right eye and 2.1 left eye. 
As shown in Table 1 , ERGs were performed on eight affected individuals (Fig. 2) , and all had normal scotopic and photopic b-wave amplitudes. Cone 30-Hz flicker amplitudes were normal in six and minimally subnormal in two; two others had slightly prolonged implicit times of 33 to 34 msec. 
Color vision for all affected individuals except one was very good or normal and did not correlate with acuity loss, as exemplified by affected male V:10 with 20/200 OD and 20/70 OS who made no errors on the D-15 test and identified correctly all 14 Ishihara plates with each eye. VI:9 was a congenital deuteranomalous male on the D-15 test. Only the severely affected 57-year-old woman (V:19) with extensive chorioretinal atrophy was unable to perform color vision testing (Table 1)
Fluorescein angiograms showed parafoveal “window defects” as an early sign of disease (Figs. 3A 3B 3C 3D 3E) , progressing to geographic macular atrophy in later stages (Figs. 3I 3J) . Most affected fundi showed peripapillary RPE atrophy. All showed slight darkening of the fluorescein angiogram background, but none had the stark black “dark choroid” that can be observed in recessive Stargardt macular degeneration. 
Results of Linkage and Haplotype Analysis
We localized this condition to chromosome 6, and markers tightly linked to retinal disease loci on this chromosome were studied further. Analysis of marker D6S271, which is linked to RDS/peripherin 4 and markers D6S275/D6S300, which are tightly linked to MCDR1/PBCRA, 9 11 15 gave two-point LOD scores of −∞ at 0.0 recombination fraction. Marker D6S280, which is linked with Stargardt-like macular degeneration, 6 gave an LOD score of 4.48 at theta = 0.05 (Table 2) . A systematic analysis was then performed by genotyping more than 40 markers between D6S402 and D6S300. The results of two-point linkage analysis with selected markers in the critical region are shown in Table 2 . The maximum LOD score of 6.55 was obtained with marker D6S1609 at 0.0 recombination. Six markers between D6S1625 and D6S1613 gave significant positive LOD scores (>3.0) at zero recombination, thus localizing the macular degeneration in this family to 6q14 (Table 2)
Figure 1 shows the haplotypes for this family. MCDR1 and PBCRA have been localized telomeric to D6S300. Affected individual V:19 and her affected son (VI:9) show recombination at D6S275. They carry the normal haplotype telomeric to this marker and thereby exclude the MCDR1/PBCRA loci from the disease gene interval in this family. The unaffected son (VI:8; age, 38 years) carries the affected haplotype between markers D6S1644 and D6S275, which places the disease-causing gene further centromeric of D6S1613. These haplotypes place the adMD locus in family UM:H785 centromeric to the published interval for MCDR1 and PBCRA (Fig. 4) . 9 11 15 The interval for CORD7 has been mapped between markers D6S430 and D6S1625. 8 Unaffected individual V:14 (age 38 years) carries the disease haplotype centromeric to D6S1707, thereby excluding the CORD7 locus from the critical region in our adMD family UM:H785. Individuals (VI:8 and V:14) underwent complete clinical examination at 38 years of age, and no abnormalities were found by ophthalmoscopy or functional testing. Both had normal fluorescein angiograms, and neither showed even early or subtle angiographic changes in the macula. The six affected family members who were seen before 40 years of age had disease changes that were easily seen on the fluorescein angiogram, even for those in their teenage years (Fig. 3) . This haplotype analysis identifies D6S1625 and D6S1613 as the flanking markers and localizes the disease-causing gene to an 8-cM region on 6q14. These results indicate that there is a third locus for macular degeneration on chromosome 6q, which is genetically distinct from CORD7 and MCDR1/PBCRA (Fig. 4)
Discussion
The gene for macular degeneration in this adMD family is localized to an 8-cM region on chromosome 6q14. This is within the 18-cM interval of STGD3 but excludes CORD7, MCDR1/PBCRA, and RDS/peripherin from the critical region. The 8-cM critical interval in this family overlaps the 16-cM region of RP25. RP25 is autosomal recessive and has “typical RP symptoms … [with] … nothing detectable by scotopic ERG,” 5 which is quite different from our family (Table 3)
CORD7 lies immediately centromeric but is excluded from the critical interval of our family. CORD7 initially shows “bull’s eye” maculopathy but progresses to advanced disease with highly attenuated rod and cone ERG responses unlike our family (Table 3) . 8 Both MCDR1 and PBCRA lie telomeric to the critical interval of our family 9 10 11 and have phenotypes different from our family. MCDR1 generally is not progressive, at least for grade 1 changes. 10 PBCRA shows extensive involvement of the nasal retina and has significant ERG abnormalities unlike our family (Table 3) . 16 The RDS/peripherin gene and the guanylate cyclase activator-1A (COD3) gene are both distant, at 6p12-p21. 4 17 The mapping interval in a pedigree with Leber phenotype of severe, global, early-age vision loss spans a 64-cM interval that overlaps 6q14, 18 but this phenotype is quite different from our family. 
The closest phenotype similarity with our family is Stargardt-like dominant macular degeneration, 6 which maps to a larger overlapping interval at 6q12–6q14. Stargardt-like macular degeneration causes considerable visual loss before 30 years of age and has progressive color vision loss proportional to the visual acuity reductions. 6 Although this seemingly is more severe than in our family, these could be allelic differences or could indicate involvement of separate genes. 
Histopathology on Stargardt macular degeneration shows accumulation of lipofuscin in RPE cells. 19 Accumulation of lipofuscin was also observed in Sorsby fundus dystrophy and Best macular degeneration. 20 21 22 Genes implicated in causing Stargardt, Sorsby, and Best macular degeneration have been identified as ATP-binding cassette transporter (ABCR), tissue inhibitor of metalloproteinases-3 (TIMP-3), and Bestrophin, respectively. 23 24 25 Although the mechanisms of these diseases are not understood yet, the products of those genes all seem to be involved in maintaining cellular integrity or dynamics. It has been speculated that the accumulation of lipofuscin in these diseases could result from accelerated turnover of photoreceptor cells; increased phagocytosis of photoreceptor outer segments; abnormal photoreceptor membranes or contents rendered indigestible by the RPE; missing or mutated degradative enzymes capable of digesting photoreceptor proteins or lipids; or failed mechanism to expel lipofuscin from the cytoplasm of RPE. 19 24 26 27 Genes or gene products involved in any of the above mechanisms that localize to the critical interval of D6S1625–D6S1613 on chromosome 6q would be good candidates for the macular degeneration in family UM:H785. Thus, genes homologous to ABCR, TIMP-3,and Bestrophin and located within the UM:H785 critical interval should be considered as candidates for mutation analysis in family UM:H785. Our search of the human expressed-sequence database at the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/cgi-bin/UniGene/) identified 115 ESTs and 16 known genes in the D6S1625–D6S1613 interval. None of these belong to the ABCR or TIMP3 family or are homologous to Bestrophin. 
The phenotype in this family is similar to STGD3, which has been reported to be allelic to CORD7. 6 7 8 Our exclusion of the CORD7 and MCDR1/PBCRA loci from the critical interval for our family UM:H785 indicates that there are at least three retinal/macular degeneration loci within 30 cM on chromosome 6 (Fig. 4) . This may signify a grouping of genes that is functionally related in a fashion similar to the HLA genes on chromosome 6p. 28 Diseases mapped to overlapping genetic interval (as is the case for STGD3, RP25, and our adMD family UM:H785) could be allelic variants of a single gene, as has been reported for RDS/peripherin phenotypes. 2 29 This can be resolved only after the genes have been cloned. 
 
Figure 1.
 
Autosomal dominant macular degeneration pedigree UM:H785 and haplotypes with 16 microsatellite markers on chromosome 6q. Squares and circles indicate males and females, respectively. Filled symbols signify affected individuals, and open symbols indicate unaffected family members. A plus sign (+) indicates that a fluorescein angiogram was obtained. Filled bars indicate the disease haplotype. Question marks in the haplotype denote polymerase chain reaction amplification failure.
Figure 1.
 
Autosomal dominant macular degeneration pedigree UM:H785 and haplotypes with 16 microsatellite markers on chromosome 6q. Squares and circles indicate males and females, respectively. Filled symbols signify affected individuals, and open symbols indicate unaffected family members. A plus sign (+) indicates that a fluorescein angiogram was obtained. Filled bars indicate the disease haplotype. Question marks in the haplotype denote polymerase chain reaction amplification failure.
Table 1.
 
Clinical Findings of Atrophic–6q14–adMD in Family UM:H785
Table 1.
 
Clinical Findings of Atrophic–6q14–adMD in Family UM:H785
Patient Age, (y) Visual Acuity Refraction Color Vision ERG Dark-Adapted Threshold Goldmann Visual Fields Comments
VI:1 15 20/50 OD 20/50 OS Plano OU D-15: no errors OU; Ishihara 13/14 correct OU Scotopic b-wave 360 μV. Photopic b-wave 116 μV. 30-Hz flicker 76 μV, 28 msec Normal Full to V4e and I4e FA: 1/4 dd foveal window defect OU. EOG 1.8 OD, 2.0 OS. Age 22 acuity 20/50 OU.
VI:2 16 20/60 OD 20/60 OS Plano OU D-15: no errors OU; Ishihara 13/14 correct OU Scotopic b-wave 230 μV. Photopic b-wave 115 μV. 30-Hz flicker 49 μV, 32 msec Normal Full to V4e and I4e FA: 1/4 dd foveal window defect OU.
V:6 15 20/30 OD 20/40 OS Plano OU D-15: one error OD; no error OS; Ishihara 14/14 correct OU. Scotopic b-wave 240 μV. Photopic b-wave 130 μV. 30-Hz flicker 65 μV, 32 msec Normal Full to V4e and I4e FA: 1/3 dd foveal window defect OU. Macular RPE granularity. Age 21 & 29 acuity 20/60 OU.
VI:9 33 20/25 OD 20/20 OS OD+1.50+ 2.00× 19 OS+0.25 D-15: congenital deuteranomally. Not performed Not performed Full to V4e and I4e FA: parafoveal window defects OU
V:2 39 20/20 OD 20/30 OS OD−3.75+ 0.75× 96 OS −4.00+ 1.25× 95 D-15: no errors OU; Ishihara 14/14 correct OU Scotopic b-wave 220 μV. Photopic b-wave 76 μV. 30-Hz flicker 51 μV, 30 msec Normal Full to V4e and I4e FA: 3/4 dd parafoveal ring window defect OU. EOG 1.9 OD, 1.8 OS. Age 43 acuity 20/25 OU.
IV:6 42 20/70 OU Plano OU D-15: no error OD; 3 error OS; Ishihara 13/14 correct OU. Scotopic b-wave 350 μV. Photopic b-wave 118 μV. 30-Hz flicker 80 μV, 34 msec Normal Full to V4e and I4e FA: foveal 1 dd atrophic window defect with parafoveal surrounding “garland” of window defects. EOG 2.2 OD, 2.1 OS. Age 49 acuity 20/200 OU.
V:10 47 20/200 OD 20/70 OS OD−1.00 sphere OS plano D-15: no errors OU; Ishihara 14/14 correct OU Scotopic b-wave 260 μV. Photopic b-wave 90 μV. 30-Hz flicker 60 μV, 32 msec Normal Full to V4e and I4e; small I4e central scotoma OU. FA: central & satellite window defects 1.5 dd OU.
V:11 51 20/20 OD 20/20 OS OU+2.75 sphere D-15: no errors OU; Ishihara 14/14 correct OU Scotopic b-wave 380 μV. Photopic b-wave 116 μV. 30-Hz flicker 80 μV, 30 msec Normal Full to V4e and I4e FA: perifoveal & macular window defects OU.
V:19 57 20/300 OU Plano OU D-15: more than 10 errors OU; Ishihara: unable to do Not performed Not performed Full to V4e and I4e; 50° central I4e scotoma FA: 1.5 dd total atrophy of RPE & choriocapillaris, with macular hyperfluorescence from confluent “flecked” defects extending to arcade vessels
IV:2 61 20/200 OU Plano OU D-15: 1 error OD; many error OS; Ishihara 12/14 OD, 13/14 OS. Scotopic b-wave 288 μV. Photopic b-wave 100 μV. 30-Hz flicker 64 μV, 33 msec Normal Full to V4e and I4e FA: 1.5 dd total atrophy of RPE & choriocapillaris surrounded by multiple, macular hyperfluorescent window defects. EOG 1.8 OU. Age 67 acuity 20/300 OU.
Figure 2.
 
ERG of eight affected individuals in atrophic-6q14-adMD pedigree UM:H785. The rod and cone ERG amplitudes are normal on all, except for 30-Hz flicker for two affected individuals who had slightly subnormal amplitudes (VI:2 and V:2) and two who had minimal implicit time delays (IV:6 and IV:2). y/o, years old.
Figure 2.
 
ERG of eight affected individuals in atrophic-6q14-adMD pedigree UM:H785. The rod and cone ERG amplitudes are normal on all, except for 30-Hz flicker for two affected individuals who had slightly subnormal amplitudes (VI:2 and V:2) and two who had minimal implicit time delays (IV:6 and IV:2). y/o, years old.
Figure 3.
 
Fluorescein angiogram of 10 male (M) and female (F) affected individuals, 15 to 61 years of age (y/o), in pedigree UM:H785. Corresponding individual number and age are shown below each angiogram. All show hyperfluorescent “window defects” in the macula. The angiograms all tend to be darker than normal, but none has a jet-black“ dark, silent choroid.”
Figure 3.
 
Fluorescein angiogram of 10 male (M) and female (F) affected individuals, 15 to 61 years of age (y/o), in pedigree UM:H785. Corresponding individual number and age are shown below each angiogram. All show hyperfluorescent “window defects” in the macula. The angiograms all tend to be darker than normal, but none has a jet-black“ dark, silent choroid.”
Table 2.
 
Two point LOD scores of microsatellite markers on chromosome 6 vs family UM:H785
Table 2.
 
Two point LOD scores of microsatellite markers on chromosome 6 vs family UM:H785
Markers Distance* (cM) Two Point lod Scores at Theta = Z max θ
0 0.05 0.1 0.2 0.3 0.4
D6S271 15.3 −∞ −0.07 0.51 0.73 0.56 0.26 0.07 0.19
D6S402 0.7 −∞ 2.13 2.13 1.53 0.77 0.18 2.18 0.07
D6S430 1.2 −∞ 2.31 2.34 1.90 1.22 0.52 2.37 0.08
D6S1557 1.4 −∞ 4.37 4.31 3.51 2.38 1.10 4.40 0.07
D6S1681 2.7 −∞ 6.18 5.78 4.59 3.14 1.54 6.24 0.03
D6S280 1.7 −∞ 4.48 4.25 3.39 2.29 1.08 4.48 0.04
D6S1589 0.0 −∞ 4.40 4.15 3.29 2.24 1.08 4.42 0.04
D6S1625 1.2 −∞ 2.70 2.60 2.08 1.42 0.68 2.70 0.06
D6S1707 1.2 0.58 0.51 0.44 0.30 0.16 0.06 0.58 0.0
D6S445 0.6 4.28 3.80 3.32 2.38 1.50 0.71 4.28 0.0
D6S1634 0.0 4.15 3.70 3.23 2.29 1.35 0.50 4.15 0.0
D6S1609 0.8 6.55 6.24 5.95 4.93 3.53 1.84 6.55 0.0
D6S1595 0.0 4.12 3.72 3.31 2.46 1.58 0.70 4.12 0.0
D6S1601 2.9 3.13 2.82 2.51 1.87 1.21 0.53 3.13 0.0
D6S1644 1.0 5.09 4.70 4.26 3.29 2.22 1.09 5.09 0.0
D6S1613 1.9 −∞ 5.05 4.72 3.69 2.46 1.10 5.07 0.04
D6S1570 1.9 −∞ 3.79 3.62 2.91 1.99 0.95 3.79 0.05
D6S1631 0.7 −∞ 4.33 4.01 3.01 1.85 0.70 4.35 0.04
D6S275 1.9 −∞ 2.93 3.04 2.59 1.81 0.87 3.05 0.09
D6S300 −∞ 0.49 0.88 1.02 0.79 0.35 1.03 0.18
Figure 4.
 
Schematic shows the retinal disease genes that map to the long arm of chromosome 6. The critical interval of RP25 extends to the 6p. 16
Figure 4.
 
Schematic shows the retinal disease genes that map to the long arm of chromosome 6. The critical interval of RP25 extends to the 6p. 16
Table 3.
 
Comparison of the Clinical Phenotype of Retinal Macular Dystrophies Mapped to Chromosome 6q
Table 3.
 
Comparison of the Clinical Phenotype of Retinal Macular Dystrophies Mapped to Chromosome 6q
adMD Stargardt-like MD 6 MCDR1 10 11 PBCRA 16 CORD7 8 RP25 5
Color vision Normal even with low acuity Becomes worse with acuity loss “Normal” “Reduced severely” “Reduced,” begin ages 20–40 y/o No information
Visual acuity 20/20–20/200 30 y/o: <20/80 40 y/o: <20/200 20/20–20/200 median: 20/40–20/60 “20/120 to counting fingers” “Reduced,” begin ages 20–40 y/o No information
Age of onset Teenage years, progressive 10–12 y/o, progressive Congenital, “not progressive” Congenital, progressive 20–40 y/o, progressive No information
Fundus examination Macular and peripapillary RPE atrophy with flecks RPE atrophy surrounded by yellow flecks in the macula 3 severity grades: 1) macular, drusen-like yellow flecks; 2) disciform lesions 3) macular coloboma Macular “punched-out area of chorioretinal atrophy,” RPE mottling nasal to disc “Retinal pigmentary changes … around the fovea simulating a bull’s eye dystrophy, which developed to macular atrophy” “Typical RP symptoms, characteristic fundus examination”
ERG Normal photopic and scotopic a- and b-waves, slightly delayed 30-Hz flicker in 3 of 8 affected family members “Mildly abnormal b-wave amplitudes for rods and cones,” some have delayed 30-Hz flicker “Normal” “Significantly diminished” rod and cone responses, “cone flicker responses grossly subnormal and delayed” “Scotopic rod responses barely detectable … cone responses severely attenuated but with no change in implicit time” “Nothing detectable by scotopic ERG”
Inheritance Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant Autosomal recessive
The authors thank Bradley B. Nelson, Caraline L. Coats, and Jennifer A. Kemp for their help in preparing the figures. 
Mah DY, Wong PW, Edwards A, MacDonald IM. Recent advances in the genetics of macular dystrophies. Can J Ophthalmol. 1998;33:135–143. [PubMed]
Weleber RG, Carr RE, Murphey WH, Sheffield VC, Stone EM. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol. 1993;111:1531–1542. [CrossRef] [PubMed]
Uliss AE, Moore AT, Bird AC. The dark choroid in posterior retinal dystrophies. Ophthalmology. 1987;94:1423–1427. [CrossRef] [PubMed]
Payne AM, Downes SM, Bessant DA, Bird AC, Bhattacharya SS. Founder effect, seen in the British population, of the 172 peripherin/RDS mutation and further refinement of genetic positioning of the peripherin/RDS gene. Am J Hum Genet. 1998;62:192–195. [CrossRef] [PubMed]
Ruiz A, Borrego S, Marcos I, Antinolo G. A major locus for autosomal recessive retinitis pigmentosa on 6q, determined by homozygosity mapping of chromosomal regions that contain gamma-aminobutyric acid-receptor clusters. Am J Hum Genet. 1998;62:1452–1459. [CrossRef] [PubMed]
Stone EM, Nichols BE, Kimura AE, Weingeist TA, Drack A, Sheffield VC. Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q. Arch Ophthalmol. 1994;112:765–772. [CrossRef] [PubMed]
Edwards OA, Miedziak A, Vrabec T, et al. Autosomal dominant Stargardt-like macular dystrophy, I: clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14 [abstract]. Am J Ophthalmol. 1999;127:426–435. [CrossRef] [PubMed]
Kelsell RE, Gregory–Evans K, Gregory CY, et al. Localization of a gene (CORD7) for a dominant cone-rod dystrophy to chromosome 6q. Am J Hum Genet. 1998;63:274–279. [CrossRef] [PubMed]
Kelsell RE, Godley BF, Evans K, et al. Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q. Hum Mol Genet. 1995;4:1653–1656. [CrossRef] [PubMed]
Small KW, Weber JL, Roses A, Lennon F, Vance JM, Pericak–Vance MA. North Carolina macular dystrophy is assigned to chromosome 6. Genomics. 1992;13:681–685. [CrossRef] [PubMed]
Sauer CG, Schworm HD, Ulbig M, et al. An ancestral core haplotype defines the critical region harbouring the North Carolina macular dystrophy gene (MCDR1). J Med Genet. 1997;34:961–966. [CrossRef] [PubMed]
Birch JM, Chisholm IA, Kinnear P, et al. Clinical testing methods. Pokorny J Smith VC Verriest G Pinckers AJLG eds. Congenital and Acquired Color Vision Defects. 1979;83–135. Academic Press London.
Padma T, Ayyagari R, Murty JS, et al. Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11–12. Am J Hum Genet. 1995;57:840–845. [PubMed]
Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984;36:460–465. [PubMed]
Small KW, Puech B, Mullen L, Yelchits S. North Carolina macular dystrophy phenotype in France maps to the MCDR1 loucs. Mol Vis. 1997;3:1. [PubMed]
Godley BF, Tiffin PA, Evans K, Kelsell RE, Hunt DM, Bird AC. Clinical features of progressive bifocal chorioretinal atrophy: a retinal dystrophy linked to chromosome 6q. Ophthalmology. 1996;103:893–898. [CrossRef] [PubMed]
Payne AM, Downes SM, Bessant DA, et al. A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Hum Mol Genet. 1998;7:273–277. [CrossRef] [PubMed]
Dharmaraj S, Robitaille JM, Zhu D, Li YY, Maumenee IH. An additional locus for Leber’s congenital amaurosis maps to chromosome 6 [ARVO Abstract]. Invest Ophthalmol Vis Sci. 1998;39(4)S296.Abstract nr 1354
Lopez PF, Maumenee IH, de la Cruz Z, Green WR. Autosomal-dominant fundus flavimaculatus: clinicopathologic correlation. Ophthalmology. 1990;97:798–809. [CrossRef] [PubMed]
Sorsby A, Mason ME, Gardener N. A fundus dystrophy with unusual features. Br J Ophthalmol. 1949;33:67–97. [CrossRef] [PubMed]
Capon MR, Marshall J, Krafft JI, Alexander RA, Hiscott PS, Bird AC. Sorsby’s fundus dystrophy: a light and electron microscopic study. Ophthalmology. 1989;96:1769–1777. [CrossRef] [PubMed]
Vail D, Shoch D. Hereditary degeneration of the macula, II: follow-up report and histopathologic study. Trans Am Ophthalmol Soc. 1965;63:51–63. [PubMed]
Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:236–246. [CrossRef] [PubMed]
Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nat Genet. 1994;8:352–356. [CrossRef] [PubMed]
Petrukhin K, Kiosti MJ, Bakall B, et al. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998;19:241–247. [CrossRef] [PubMed]
Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell. 1999;98:13–23. [CrossRef] [PubMed]
Birnbach CD, Jarvelainen M, Possin DE, Milam AH. Histopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus. Ophthalmology. 1994;101:1211–1219. [CrossRef] [PubMed]
Powis SH, Geraghty DE. What is the MHC?. Immunol Today. 1995;16:466–468. [CrossRef] [PubMed]
Wells J, Wroblewski J, Keen J, et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet. 1993;3:213–218. [CrossRef] [PubMed]
Figure 1.
 
Autosomal dominant macular degeneration pedigree UM:H785 and haplotypes with 16 microsatellite markers on chromosome 6q. Squares and circles indicate males and females, respectively. Filled symbols signify affected individuals, and open symbols indicate unaffected family members. A plus sign (+) indicates that a fluorescein angiogram was obtained. Filled bars indicate the disease haplotype. Question marks in the haplotype denote polymerase chain reaction amplification failure.
Figure 1.
 
Autosomal dominant macular degeneration pedigree UM:H785 and haplotypes with 16 microsatellite markers on chromosome 6q. Squares and circles indicate males and females, respectively. Filled symbols signify affected individuals, and open symbols indicate unaffected family members. A plus sign (+) indicates that a fluorescein angiogram was obtained. Filled bars indicate the disease haplotype. Question marks in the haplotype denote polymerase chain reaction amplification failure.
Figure 2.
 
ERG of eight affected individuals in atrophic-6q14-adMD pedigree UM:H785. The rod and cone ERG amplitudes are normal on all, except for 30-Hz flicker for two affected individuals who had slightly subnormal amplitudes (VI:2 and V:2) and two who had minimal implicit time delays (IV:6 and IV:2). y/o, years old.
Figure 2.
 
ERG of eight affected individuals in atrophic-6q14-adMD pedigree UM:H785. The rod and cone ERG amplitudes are normal on all, except for 30-Hz flicker for two affected individuals who had slightly subnormal amplitudes (VI:2 and V:2) and two who had minimal implicit time delays (IV:6 and IV:2). y/o, years old.
Figure 3.
 
Fluorescein angiogram of 10 male (M) and female (F) affected individuals, 15 to 61 years of age (y/o), in pedigree UM:H785. Corresponding individual number and age are shown below each angiogram. All show hyperfluorescent “window defects” in the macula. The angiograms all tend to be darker than normal, but none has a jet-black“ dark, silent choroid.”
Figure 3.
 
Fluorescein angiogram of 10 male (M) and female (F) affected individuals, 15 to 61 years of age (y/o), in pedigree UM:H785. Corresponding individual number and age are shown below each angiogram. All show hyperfluorescent “window defects” in the macula. The angiograms all tend to be darker than normal, but none has a jet-black“ dark, silent choroid.”
Figure 4.
 
Schematic shows the retinal disease genes that map to the long arm of chromosome 6. The critical interval of RP25 extends to the 6p. 16
Figure 4.
 
Schematic shows the retinal disease genes that map to the long arm of chromosome 6. The critical interval of RP25 extends to the 6p. 16
Table 1.
 
Clinical Findings of Atrophic–6q14–adMD in Family UM:H785
Table 1.
 
Clinical Findings of Atrophic–6q14–adMD in Family UM:H785
Patient Age, (y) Visual Acuity Refraction Color Vision ERG Dark-Adapted Threshold Goldmann Visual Fields Comments
VI:1 15 20/50 OD 20/50 OS Plano OU D-15: no errors OU; Ishihara 13/14 correct OU Scotopic b-wave 360 μV. Photopic b-wave 116 μV. 30-Hz flicker 76 μV, 28 msec Normal Full to V4e and I4e FA: 1/4 dd foveal window defect OU. EOG 1.8 OD, 2.0 OS. Age 22 acuity 20/50 OU.
VI:2 16 20/60 OD 20/60 OS Plano OU D-15: no errors OU; Ishihara 13/14 correct OU Scotopic b-wave 230 μV. Photopic b-wave 115 μV. 30-Hz flicker 49 μV, 32 msec Normal Full to V4e and I4e FA: 1/4 dd foveal window defect OU.
V:6 15 20/30 OD 20/40 OS Plano OU D-15: one error OD; no error OS; Ishihara 14/14 correct OU. Scotopic b-wave 240 μV. Photopic b-wave 130 μV. 30-Hz flicker 65 μV, 32 msec Normal Full to V4e and I4e FA: 1/3 dd foveal window defect OU. Macular RPE granularity. Age 21 & 29 acuity 20/60 OU.
VI:9 33 20/25 OD 20/20 OS OD+1.50+ 2.00× 19 OS+0.25 D-15: congenital deuteranomally. Not performed Not performed Full to V4e and I4e FA: parafoveal window defects OU
V:2 39 20/20 OD 20/30 OS OD−3.75+ 0.75× 96 OS −4.00+ 1.25× 95 D-15: no errors OU; Ishihara 14/14 correct OU Scotopic b-wave 220 μV. Photopic b-wave 76 μV. 30-Hz flicker 51 μV, 30 msec Normal Full to V4e and I4e FA: 3/4 dd parafoveal ring window defect OU. EOG 1.9 OD, 1.8 OS. Age 43 acuity 20/25 OU.
IV:6 42 20/70 OU Plano OU D-15: no error OD; 3 error OS; Ishihara 13/14 correct OU. Scotopic b-wave 350 μV. Photopic b-wave 118 μV. 30-Hz flicker 80 μV, 34 msec Normal Full to V4e and I4e FA: foveal 1 dd atrophic window defect with parafoveal surrounding “garland” of window defects. EOG 2.2 OD, 2.1 OS. Age 49 acuity 20/200 OU.
V:10 47 20/200 OD 20/70 OS OD−1.00 sphere OS plano D-15: no errors OU; Ishihara 14/14 correct OU Scotopic b-wave 260 μV. Photopic b-wave 90 μV. 30-Hz flicker 60 μV, 32 msec Normal Full to V4e and I4e; small I4e central scotoma OU. FA: central & satellite window defects 1.5 dd OU.
V:11 51 20/20 OD 20/20 OS OU+2.75 sphere D-15: no errors OU; Ishihara 14/14 correct OU Scotopic b-wave 380 μV. Photopic b-wave 116 μV. 30-Hz flicker 80 μV, 30 msec Normal Full to V4e and I4e FA: perifoveal & macular window defects OU.
V:19 57 20/300 OU Plano OU D-15: more than 10 errors OU; Ishihara: unable to do Not performed Not performed Full to V4e and I4e; 50° central I4e scotoma FA: 1.5 dd total atrophy of RPE & choriocapillaris, with macular hyperfluorescence from confluent “flecked” defects extending to arcade vessels
IV:2 61 20/200 OU Plano OU D-15: 1 error OD; many error OS; Ishihara 12/14 OD, 13/14 OS. Scotopic b-wave 288 μV. Photopic b-wave 100 μV. 30-Hz flicker 64 μV, 33 msec Normal Full to V4e and I4e FA: 1.5 dd total atrophy of RPE & choriocapillaris surrounded by multiple, macular hyperfluorescent window defects. EOG 1.8 OU. Age 67 acuity 20/300 OU.
Table 2.
 
Two point LOD scores of microsatellite markers on chromosome 6 vs family UM:H785
Table 2.
 
Two point LOD scores of microsatellite markers on chromosome 6 vs family UM:H785
Markers Distance* (cM) Two Point lod Scores at Theta = Z max θ
0 0.05 0.1 0.2 0.3 0.4
D6S271 15.3 −∞ −0.07 0.51 0.73 0.56 0.26 0.07 0.19
D6S402 0.7 −∞ 2.13 2.13 1.53 0.77 0.18 2.18 0.07
D6S430 1.2 −∞ 2.31 2.34 1.90 1.22 0.52 2.37 0.08
D6S1557 1.4 −∞ 4.37 4.31 3.51 2.38 1.10 4.40 0.07
D6S1681 2.7 −∞ 6.18 5.78 4.59 3.14 1.54 6.24 0.03
D6S280 1.7 −∞ 4.48 4.25 3.39 2.29 1.08 4.48 0.04
D6S1589 0.0 −∞ 4.40 4.15 3.29 2.24 1.08 4.42 0.04
D6S1625 1.2 −∞ 2.70 2.60 2.08 1.42 0.68 2.70 0.06
D6S1707 1.2 0.58 0.51 0.44 0.30 0.16 0.06 0.58 0.0
D6S445 0.6 4.28 3.80 3.32 2.38 1.50 0.71 4.28 0.0
D6S1634 0.0 4.15 3.70 3.23 2.29 1.35 0.50 4.15 0.0
D6S1609 0.8 6.55 6.24 5.95 4.93 3.53 1.84 6.55 0.0
D6S1595 0.0 4.12 3.72 3.31 2.46 1.58 0.70 4.12 0.0
D6S1601 2.9 3.13 2.82 2.51 1.87 1.21 0.53 3.13 0.0
D6S1644 1.0 5.09 4.70 4.26 3.29 2.22 1.09 5.09 0.0
D6S1613 1.9 −∞ 5.05 4.72 3.69 2.46 1.10 5.07 0.04
D6S1570 1.9 −∞ 3.79 3.62 2.91 1.99 0.95 3.79 0.05
D6S1631 0.7 −∞ 4.33 4.01 3.01 1.85 0.70 4.35 0.04
D6S275 1.9 −∞ 2.93 3.04 2.59 1.81 0.87 3.05 0.09
D6S300 −∞ 0.49 0.88 1.02 0.79 0.35 1.03 0.18
Table 3.
 
Comparison of the Clinical Phenotype of Retinal Macular Dystrophies Mapped to Chromosome 6q
Table 3.
 
Comparison of the Clinical Phenotype of Retinal Macular Dystrophies Mapped to Chromosome 6q
adMD Stargardt-like MD 6 MCDR1 10 11 PBCRA 16 CORD7 8 RP25 5
Color vision Normal even with low acuity Becomes worse with acuity loss “Normal” “Reduced severely” “Reduced,” begin ages 20–40 y/o No information
Visual acuity 20/20–20/200 30 y/o: <20/80 40 y/o: <20/200 20/20–20/200 median: 20/40–20/60 “20/120 to counting fingers” “Reduced,” begin ages 20–40 y/o No information
Age of onset Teenage years, progressive 10–12 y/o, progressive Congenital, “not progressive” Congenital, progressive 20–40 y/o, progressive No information
Fundus examination Macular and peripapillary RPE atrophy with flecks RPE atrophy surrounded by yellow flecks in the macula 3 severity grades: 1) macular, drusen-like yellow flecks; 2) disciform lesions 3) macular coloboma Macular “punched-out area of chorioretinal atrophy,” RPE mottling nasal to disc “Retinal pigmentary changes … around the fovea simulating a bull’s eye dystrophy, which developed to macular atrophy” “Typical RP symptoms, characteristic fundus examination”
ERG Normal photopic and scotopic a- and b-waves, slightly delayed 30-Hz flicker in 3 of 8 affected family members “Mildly abnormal b-wave amplitudes for rods and cones,” some have delayed 30-Hz flicker “Normal” “Significantly diminished” rod and cone responses, “cone flicker responses grossly subnormal and delayed” “Scotopic rod responses barely detectable … cone responses severely attenuated but with no change in implicit time” “Nothing detectable by scotopic ERG”
Inheritance Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant Autosomal recessive
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