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Autosomal Dominant Stargardt-like Macular Dystrophy
Founder Effect and Reassessment of Genetic Heterogeneity
Larry A. Donoso, MD, PhD;
Arcilee T. Frost, MA;
Edwin M. Stone, MD, PhD;
Richard G. Weleber, MD;
Ian M. MacDonald, MD;
Gregory S. Hageman, PhD;
Gerhard W. Cibis, MD;
Robert Ritter III, MS;
Albert O. Edwards, MD, PhD
Arch Ophthalmol. 2001;119:564-570.
ABSTRACT
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Objectives To characterize a disease-associated haplotype in 7 families with autosomal
dominant Stargardt-like macular dystrophy and to determine whether these families
share a common ancestor.
Methods Twenty-five polymorphic DNA markers spanning known dominant Stargardt-like
gene loci were used to determine the haplotype associated with disease. In
addition, an extensive genealogical investigation searching for a common ancestor
shared by all of the 7 families was performed.
Results We clinically evaluated 171 patients and genotyped 145 samples. The
same DNA haplotype on chromosome 6q16 was shared by all evaluated affected
members within the 7 families. In addition, we were able to genealogically
join all of the families into one larger family consisting of 31 branches
and 2314 individuals. Twenty-seven branches have known living descendants,
with 7 branches having affected family members. In addition, we refined the
critical region for the gene to approximately 1000 kilobases (kb) and eliminated
part or all of 9 candidate disease-causing genes.
Conclusions Our study indicates that most reported cases of autosomal dominant Stargardt-like
macular dystrophy in North America are part of a single larger family associated
with a gene locus on chromosome 6q16. Furthermore, the DNA haplotype associated
with disease is useful in excluding individuals with phenotypically similar
retinal conditions.
Clinical Relevance The disease-associated haplotype allows for more accurate genetic counseling
to be given to individuals with a Stargardt-like phenotype inherited in an
autosomal dominant pattern.
INTRODUCTION
FAMILIES affected by rare hereditary diseases are often described independently
and are usually unrelated. However, molecular genetic studies can determine
whether such families share a related genomic DNA region containing the disease
locus. Such findings imply that the disease actually arose in a common ancestor
or founder. For example, Fingert and associates1
found all 27 glaucoma families affected with the GLN386STOP mutation in the
myocilin gene appeared to be related through a common ancestor even though
they were identified in 4 different patient populations. Equally striking
is the observation that all 39 families with radial drusen (malattia leventinese
or Doyne honeycomb retinal dystrophy) share a single identical mutation in
the EFEMP1 gene containing the same pattern of DNA
sequence variation (haplotype).2 Thus, the
radial drusen mutation appears to have arisen once in an ancestor shared by
all 39 families who lived on 3 different continents.
Autosomal dominant Stargardt-like macular dystrophy is another rare
hereditary retinal disease reported as occurring independently in several
families.3-13
Clinically, the disease usually presents in the teenage years with decreased
visual acuity and atrophy of the macular retinal pigment epithelium with or
without surrounding subretinal flecks and progresses rapidly over several
years to legal blindness. In 1980, Cibis et al8
described one such large family consisting of 98 at-risk members. Several
other families with similar clinical features were subsequently described.3, 6-7,9 More
recently, we described the clinical and genetic features of 4 large families
living in the United States.10-13
Two of these families were found to share a common set of DNA markers (disease-associated
haplotype) in the disease gene region of chromosome 6 as well as paternal
ancestors, raising the possibility that other families with dominant Stargardt-like
dystrophies might be related.12 In this study,
we show that 7 affected families are part of a single, larger family consisting
of more than 2000 individuals whose affected members share an identical disease-associated
haplotype spanning the gene responsible for this condition located on chromosome
6q16.
PATIENTS AND METHODS
The patients in this study comprise one single family. There are 31
branches of this family, with 7 branches (Figure 1) having affected members. Each of the 7 affected families
were thought to be independent of one another before this study, and all were
diagnosed as having autosomal dominant Stargardt-like macular dystrophy. We
use the term family to refer to the descendants of
the top generation of a pedigree known to the authors at the time they reported
the pedigree. When independently identified families are found to be related
through genetic analysis or genealogical investigation, we refer to the original
families as branches of a new larger family.
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Figure 1. Diagram and pedigree depicting
founding family and 31 branches. Circle indicates female; square, male; filled
circle or square, affected individual; and diagonal line, deceased individual.
Thick arrow indicates branch with known macular dystrophy; thin arrow, branch
with no known macular dystrophy; and arrowhead, branch with no known descendants.
Numbers at bottom correspond to branch of family. Numbers in parentheses indicate
an individual family member. For more details concerning branch 5, see Lagali
et al;13 branches 13 and 14, see Edwards et
al;12 branch 24, see Stone et al;10
and branch 30, see Zhang et al.11 Information
on branches 10 and 20 has not been previously published.
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One hundred seventy-one patients at risk for developing the disease
were examined. Patients were considered affected if they showed progressive
bilateral visual loss of early onset and if they had atrophic macular lesions
as previously described.10, 12
In all cases, the disease status was determined before genotyping and examination.
In cases where the patient had died, the disease status was inferred by clinical
history or medical and/or governmental records. This study was approved by
the institutional review board at each institution.
Family records were searched at the facilities of the Latter Day Saints
Family History Center in Salt Lake City, Utah. Additional information was
obtained from interviews with family members and from records from city, state,
and federal agencies. Marriage, death, cemetery, census, hospital, and church
records were also searched. Although more than 3500 family records were obtained,
we include only families with direct links to the founder.
Genomic DNA was obtained from peripheral blood and extracted using standard
techniques (QIAmp Blood MIDI kit; Qiagen, Inc, Santa Barbara, Calif). Of the
27 branches with living descendants, at least 1 sample was obtained from 16
branches. One hundred forty-five samples were genotyped. Genotypes at polymorphic
short tandem repeat markers spanning the disease loci on chromosomes 6q16
(13 markers) and 13q34 (12 markers) were determined in selected patients as
previously described.10-12
Haplotypes were constructed manually and/or by using the algorithm used in
the GENEHUNTER software package.14 The disease-associated
haplotype is that set of 13 DNA markers on chromosome 6, which segregates
in association with dominant Stargardt-like macular dystrophy. The disease
penetrance was estimated from the age of disease onset. The penetrances used
were as follows: age 0 to 10 years, 0.62; age 11 to 20 years, 0.90; age 21
years or older, 0.99; with a disease allele frequency of 0.000001. Two-point
linkage analysis was performed in selected members (60 family members) of
branches 13, 14, and 30 using 3 chromosome 6 (D6S286, D6S460, and D6S1609)
and 3 chromosome 13 (D13S158, D13S173, and D13S280) markers using the methods
as previously described.10
RESULTS
DESCRIPTION OF APPARENTLY INDEPENDENT FAMILIES
The phenotypic appearance and the disease-associated haplotype were
determined in these 7 apparently unrelated families (Table 1). The disease-associated haplo-type was useful in combining
the families into one larger family, excluding families with this diagnosis
from other families, and refining the chromosomal location of the gene responsible
for this condition. The results correlated with the genealogical analysis
as described herein.
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Table 1. Summary of Family
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PHENOTYPIC APPEARANCE
The clinical course of disease and the phenotypic appearance of the
fundus were similar in most patients within the 7 affected families, although
some variations were observed (Figure 2).10, 12 Early disease was characterized by
subfoveal atrophy of the retinal pigment epithelium with or without the presence
of flecks. Later in the disease, the foveal lesions were more pronounced,
often with a beaten-metal appearance. At this stage, most of the patients
demonstrated subretinal flecks. Patients with late-stage disease often show
diffuse geographic atrophy with or without flecks (Figure 2).
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Figure 2. Representative fundus photographs
of patients with autosomal dominant Stargardt-like macular dystrophy showing
atrophy of the retinal pigment epithelium centered on the fovea and surrounding
subretinal flecks. A, Branch 30 (see Zhang et al11);
B, branch 14; C, branch 5; and D, branch 24. Note similarity of phenotype
with foveal atrophy and flecks.
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A SINGLE LARGER FAMILY
An identical chromosome 6q16 pattern of DNA markers (haplotype) segregated
with the disease gene (Figure 3)
in all affected members of all families studied (branches 5, 10, 13, 14, 20,
24, and 30) but not in any of the unaffected family members. The probability
of 2 individuals sharing this same disease-associated haplotype by chance
is highly unlikely (approximately 1 in 100 trillion).10
This result indicates that these 7 affected families (1237 total members)
are genetically related through a common ancestor or founder. Nonaffected
family members or other family members with juvenile-onset visual loss, including
one case of a patient with a childhood intraocular inflammatory disease and
one patient with foveal hypoplasia and nystagmus (Table 1; branches 1 and 22), did not share the haplotype.
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Figure 3. Segregation of chromosomal markers.
Although a chromosome 13 haplotype (solid blue bar; see Zhang et al11) appears to segregate with the disease locus (V:8,
VI:7, and VII:8), the absence of any portion of this haplotype from other
members of the family (VIII:1, IX:1, VIII:4, and VII:6) excludes the disease-causing
gene from this region. Conversely, all affected patients in all families with
disease segregate chromosome 6 markers (solid black bar) with the disease.
The markers used for chromosome 6 were D6S430, D6S313, D6S1681, D6S280, D6S286,
D6S460, D6S1609, D6S1601, D6S462, D6S275, D6S417, D6S1720, and D6S300. The
markers used for chromosome 13 were D13S154, D13S1252, D13S1284, D13S159,
D13S1267, D13S1240, D13S158, D13S1256, D13S174, D13S280, D13S1322, and D13S1311.
The numbers adjacent to the solid bars correspond to the haplotype associated
with chromosome 6 and 13 markers, respectively. The symbols are described
in the legend to Figure 1.
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It became apparent during our genealogical investigation (see the following
section) that branch 30 represented a family that was previously described
to exhibit linkage between the disease and markers on chromosome 13. Records
were identified in this study showing ancestors from this branch lived on
a farm adjacent to other family branches (13, 14, and 24) in the early 1800s,
confirming the potential for marriage relationships. Maximal 2-point lod scores
at a  of 0.0 for the 3 chromosome 6 markers were 7.47, 12.24, and
7.49. Removing branch 30 reduced the lod scores to 5.77, 10.72, and 6.11,
respectively. The 2-point lod scores at a of 0.0/0.1 for the 3 chromosome
13 markers were -27.91/-2.05, -4.88/0.97, and -6.03/0.20,
demonstrating exclusion of the chromosome 13 interval. The lod scores without
branch 30 were comparable. The chromosome 6 disease-associated haplotype was
present in all affected family members of this branch studied.
REFINEMENT OF CRITICAL REGION AND SCREENING OF CANDIDATE GENES
Analysis of the recombinant individuals within our 7 families with affected
individuals enabled us to refine the genomic location of the gene on chromosome
6q16. As illustrated in Figure 4,
the critical region is estimated to be approximately 1000 kilobases (kb) using
recombinant data from affected and unaffected individuals. The critical region
using only affected individuals is also illustrated. Twenty-seven new short
tandem repeat markers were developed using genomic sequence from the Sanger
Centre
(http://www.sanger.ac.uk/) to facilitate the refinement.
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Figure 4. The refined critical region of
STG3 is approximately 1000 kilobases (kb). New short tandem repeat polymorphic
markers were identified to refine the disease locus of STG3. The centromeric
boundary at 551A13.A is defined by a normal recombinant (99111). Another normal
recombinant individual (2022), approximately 30-kb telomeric to 551A13.A at
551A13.C, confirms this refinement. These 2 individuals exclude HTR1B and
all centromeric genes. The telomeric boundary of the refined critical region
is defined by an affected individual (3015) at 260P22.A. This excludes all
genes telomeric to and part of BCKDH E1. Twelve unidentified transcripts,
probably representing 6 genes, and 4 known genes lie within this region. The
Sanger Centre has sequenced a group of overlapping clones spanning the region
with 2 gaps as of September 7, 2000.
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During refinement of the critical region, we screened coding sequence
in 9 genes. The status of our screening using DNA sequencing of gene exons
from 1 unaffected and 1 affected individual is shown in Table 2. At this time, we have excluded coding sequence variations
in the human kinase gene (TTK), 3 of 4 exons in a
novel protein similar to SH3BGR (75K24.1 in the Sanger database), an unnamed
protein (complementary DNA accession AK000712) except for exon 8, and thyroid
receptor interacting protein (TRIP7).
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Table 2. Summary of Candidate Gene Analysis*
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GENEALOGICAL ANALYSIS OF APPARENTLY INDEPENDENT FAMILIES
Having demonstrated that all of the families studied herein were genetically
related through a common founder, we performed an extensive genealogical investigation
to identify the relationships between the families. This investigation revealed
that all of the families with disease reported herein can be traced to the
marriage in 1789 between individuals III:14 and III:15 (Figure 1). This marriage resulted in 31 family branches (Figure 1), giving rise to a total of 2314
descendants (Table 1). The total
number of family members ranged from 1 (branches 11, 12, 21, and 23) to 457
(branch 24) members per branch (Table 1). Four of the 31 branches (11, 12, 21, and 23) did not give rise
to any descendants. Two branches (1 and 22) gave rise to descendants with
early-onset visual loss unrelated to macular dystrophy.
Seven branches, designated as 5, 10, 13, 14, 20, 24, and 30, have descendants
with autosomal dominant Stargardt-like macular dystrophy (Table 1 and Figure 1).
This includes approximately 200 affected individuals (approximately 170 known
living). Branch 5 has not been described previously and consists of 66 members.
Branches 13 and 14 consist of 238 and 179 members, respectively (Table 1). Branch 20 is composed of 37 members
and has not been described previously. Branch 24 is composed of 457 individuals
and represents the largest known branch. Branch 30 is composed of 157 members.
One branch, designated branch 10, has no known living descendants with the
condition. Affected members from this branch were previously evaluated (1964)
at the University of Iowa Hospitals and Clinics.
COMMENT
Our study demonstrates that most families in the United States and Canada
with members diagnosed as having autosomal dominant Stargardt-like macular
dystrophy are related and comprise a single larger family. One of the unifying
clinical features we observed independently was the similar phenotypic appearance
and clinical course of this disorder among the various affected members of
the 7 families.10-13
These features included the early onset of progressive visual loss associated
with bilateral foveal atrophy with or without fundus flecks. However, a dark
choroid on fluorescein angiography was not a feature of this family as has
been observed in a substantial fraction of patients with recessive Stargardt
macular dystrophy. These relationships among independently described families
were further demonstrated by a combination of molecular genetic and genealogical
approaches.
A prominent molecular genetic feature of all 7 families was that they
shared an identical DNA haplotype on chromosome 6. This result indicated that
all 7 families descended from a common ancestor or founder. The chance of
2 individuals having this same disease-associated haplotype is extremely small.
A family from which all of these families arose was subsequently identified
genealogically.
Although the size of the family reported herein is large, we are aware
of other families9, 15-16
that have been reported to link to chromosome 6. Based on our results, it
is likely that some of these families may also be related to our family, resulting
in an even larger family. This is further supported by our genealogical findings
in that we only traced the descendants from one marriage (Figure 1; individuals III:14 and III:15). Since individuals III:14
and III:15 had a total of 16 brothers and sisters, it is likely that several
additional families (of either the paternal or maternal line) gave rise to
other descendants with this condition. A genealogic investigation of these
descendants is currently in progress.
All reported linkage studies10, 12
on families with autosomal dominant Stargardt-like macular dystrophy, which
are available to us, have localized the disease gene to chromosome 6. Zhang
and associates11 previously reported linkage
to chromosome 13 in branch 30. Our results, based on genealogical and molecular
genetic findings, indicate that this branch also is part of the family described
herein. Ultimately, the genetic defect in this disorder will rely on the identification
of the actual disease-causing gene and will help clarify this discrepancy.
Although the genetic defect has not been identified to date in this
disorder, our results have narrowed the genetic interval for the disease-causing
gene on chromosome 6 to approximately 1000 kb. Several candidate genes (Table 2) in this interval, including Col12A1 (collagen-associated gene), SSP1 (protein kinase gene), MYO6 (myosin 6
gene), TTK (human kinase gene), and TRIP7 (thyroid receptor interacting protein), were screened, and no
mutations were identified that correlated with disease status.
Although the current population of the United States is relatively diverse,
the early settlement of the country occurred in well-defined movements. One
such movement, the Great Scottish-Irish Movement, occurred in the mid-1700s
primarily through Pennsylvania before settling in stages to the west and south.17 All of the families identified in our study, including
individuals III:14 and III:15 (Figure 1),
appear to have originated from this Scottish-Irish movement. Furthermore,
the 31 branches of this family appear to have settled in a relatively narrow
region in the United States, with most of the known families living within
the same or adjacent states.
In one branch (10), there were no living descendants with macular dystrophy
to study. This finding indicates other additional families with this condition
may have existed or have not been uncovered to date. Furthermore, it is not
always possible to determine the disease status of early ancestors. This is
true in our study as well. However, in some cases, it is possible to infer
it from vital records. For example, 2 individuals were mustered out of the
US Army during the Civil War and received pensions at ages 17 and 18 years
because of blindness, implying they inherited the disease genotype.
The identification and characterization of this large family will be
useful both clinically and in studies directed toward identifying the gene
responsible for this disorder. The finding that many of these patients are
related and share an identical disease-associated haplotype will also be useful
in counseling families carrying the gene for this condition.
AUTHOR INFORMATION
Accepted for publication December 14, 2000.
This study was supported in part by the Henry and Corinne Bower Laboratory
for Macular Degeneration, Philadelphia, Pa; the Elizabeth C. King Trust, the
estates of Margaret Mercer, Harry B. Wright, Reuben and Mollie Gordon Foundation,
and Martha W. S. Rogers, and Research to Prevent Blindness Inc (RPB) (University
of Texas Southwestern Medical Center, the University of Iowa, and Wills Eye
Hospital); a career development award from RPB and the Foundation Fighting
Blindness (Dr Edwards); the Association for Macular Diseases, Macular Degeneration
International, the Kyle Curran Memorial Fund for Juvenile Macular Degeneration
(Dr Weleber); Foundation Fighting Blindness; and National Institutes of Health
grants EY11515 (Dr Hageman), EY10539 (Dr Stone), and EY12699 (Drs Edwards
and Donoso). Dr Donoso is the Thomas D. Duane Professor of Ophthalmology,
Wills Eye Hospital and Jefferson Medical College, Thomas Jefferson University.
Wallace McMeel, MD, provided helpful discussions and Kang Zhang, MD,
provided a fundus photograph. Dale Drake and Robert Andrew provided genealogical
assistance. The sequence data were produced by the human chromosome 6 sequencing
group at the Sanger Centre, Wellcome Trust Genomic Centre, Hinxton, Cambridge,
England.
Corresponding author and reprints: Albert O. Edwards, MD, PhD, Department
of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry
Hines Blvd, Dallas, TX 75390-9057 (e-mail: Albert.Edwards{at}UTSouthwestern.edu).
From the Henry and Corinne Bower Laboratory, Wills Eye Hospital, Philadelphia,
Pa (Dr Donoso and Ms Frost); Department of Ophthalmology and Visual Sciences,
The Center for Macular Degeneration, University of Iowa, Iowa City (Drs Stone
and Hageman); Casey Eye Institute, Oregon Health Sciences Center, Portland
(Dr Weleber); Department of Ophthalmology, University of Alberta, Edmonton
(Dr MacDonald); Children's Mercy Hospital, Kansas City, Kan (Dr Cibis); and
the Department of Ophthalmology, University of Texas Southwestern Medical
Center, Dallas (Mr Ritter and Dr Edwards). The authors have no financial interest
in any product or company mentioned in this article.
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SECTION EDITOR: EDWIN M. STONE, MD, PHD
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