American Journal of Medical Genetics 76:438445 (1998)

Founder Effect in GLC1A-Linked Familial

Open-Angle Glaucoma in Northern France
Antoine P. Brezin,1 Marie F. Adam,1 Ahmed Belmouden,1 Marie-Aude Lureau,1 Andre Chaventre,2
Bruno Copin,1 Lucienne Gomez,1 Stephane Dupont de Dinechin,1 Merouane Berkani,1,3
Francoise Valtot,3 Jean-Francois Rouland,4 Jean-Claude Dascotte,4 Jean-Francois Bach,1 and
Henri-Jean Garchon1*
1

INSERM U25, Paris, France

Laboratoire danthropologie et de demographie genetiques, Universite Bordeaux 2, Bordeaux, France
3
Institut du Glaucome, Hopital Saint-Joseph, Paris, France
4
Service dophtalmologie, C.H.U. Lille, Lille, France
2

Open-angle glaucoma (POAG) is a highly

prevalent cause of visual impairment. Six
families grouping 71 living patients affected
with juvenile-onset and middle-age POAG
(age at diagnosis ranging from 10 to 65
years) were linked to the GLC1A locus. All
patients carried a mutation of an evolutionarily conserved asparagine residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain, which is encoded
by the third exon of the GLC1A gene. The
N480K mutation was also identified in 14
unaffected carriers who are at high risk of
developing POAG. Although four of the
families had ancestors identified in Northern France, the pedigrees could not be interconnected by genealogical investigation.
However, haplotype analysis indicated that
all the carriers had inherited the N480K mutation from the same founder. Screening of a
selected set of 67 POAG patients who originated from Northern France and underwent
trabeculectomy before the age of 50, detected one patient with the N480K mutation
associated with the same disease haplotype
already characterized in the 6 families. This
group of 72 POAG patients is the largest one
having a GLC1A mutation in common and
provides a unique tool to investigate the factors influencing the variable expressivity of
the GLC1A gene. Am. J. Med. Genet. 76:438
445, 1998. 1998 Wiley-Liss, Inc.

Contract grant sponsor: INSERM; Contract grant sponsor: Association pour la Recherche en Genetique Ophtalmologique; Contract grant sponsor: GREG-genome; Contract grant sponsor: Mutuelle Generale de lEducation Nationale.
*Correspondence to: Henri-Jean Garchon, INSERM U25, Hopital Necker, 161 rue de Se`vres, 75743 Paris, Cedex 15, France.
E-mail: garchon@necker.fr
Received 10 September 1997; Accepted 12 December 1997

1998 Wiley-Liss, Inc.

KEY WORDS: o p e n - a n g l e g l a u c o m a ;
GLC1A; unaffected carriers;
founder effect

INTRODUCTION
Primary open-angle glaucoma (POAG) is a highly
prevalent optic neuropathy and a leading cause of irreversible blindness in industrialized countries [Leske,
1983]. Its definition associates characteristic cupping
of the optic disc and alteration of the visual field [Quigley, 1993]. Intraocular pressure (IOP) is often elevated
and is a major risk factor [Quigley, 1993]. Prognosis is
strongly dependent on diagnosis at an early stage,
when treatment can prevent irreversible lesions of the
optic nerve [Kass et al., 1989].
Family history is another major risk factor of POAG
[Leske, 1983]. The juvenile-onset form of POAG is often
inherited in an autosomal dominant mode [Johnson et
al., 1993] and a locus, termed GLC1A, has been
mapped to chromosome 1q21-q31 [Sheffield et al.,
1993]. The GLC1A region was progressively restricted
to a 3-cM interval, corresponding to a physical size of 3
Mbases [Belmouden et al., 1997]. Recently, the Trabecular Meshwork Induced Glucocorticoid Response Protein (TIGR) gene was identified as the GLC1A gene
responsible for the disease in several American families and in unrelated POAG patients [Stone et al.,
1997]. Besides its importance for understanding the
pathogenesis of glaucoma, this discovery has major
clinical implications. Direct detection of GLC1A mutations should facilitate the identification of GLC1Alinked families, regardless of their size, and the screening of mutation carriers. This is of particular importance as the risk of developing a severe glaucomatous
optic neuropathy was shown to be greater in GLC1Alinked than in GLC1A-unlinked families [Brezin et al.,
1997].
Initial studies of GLC1A-linked families described a
typical clinical profile with onset before the age of 20,
highly elevated IOP, rapid loss of visual field, con-

Founder Effect in Familial POAG

trolled only by surgical treatment [Sheffield et al.,

1993; Richards et al., 1994; Wiggs et al., 1994; Graff et
al., 1995]. Subsequently, the range of phenotypes encompassed by the GLC1A gene was extended. Two
large families with both juvenile-onset and middle-ageonset POAG cases were linked to GLC1A, suggestive of
variable expressivity of this gene in these families
[Morissette et al., 1995; Meyer et al., 1996]. A mutation
of the GLC1A gene, Gln368Stop, was also characterized in unrelated adult POAG patients [Stone et al.,
1997]. The factors that determine the variable expression of the GLC1A gene remain to be identified. Their
knowledge would be most useful, notably for anticipating onset of disease in mutation carriers. As a first
step to studying these factors, we have characterized 6
POAG families grouping 71 patients with age at diagnosis ranging from 10 to 65 years and all carrying the
same mutation inherited from a common founder.
MATERIALS AND METHODS
Patients and Families
Participating persons were most often contacted
through another member of their family. Their informed consent was obtained in keeping with French
legislation. A total of 144 subjects underwent examination by at least one of us (F.V., J.C.D., J.F.R., M.B., and
A.P.B.). Complete examination included slit-lamp biomicroscopy, gonioscopy, funduscopy with a threemirror lens, IOP measurement with a Goldmann applanation tonometer, and automated perimetry. For
other subjects, clinical records were requested from local ophthalmologists. POAG was diagnosed by the conjunction of open-angle gonioscopy and characteristic
cupping of the optic disc with a loss of visual field.
Family 14 was presented previously [Family C in Brezin et al., 1997].

439

PCR Amplification of Polymorphic Markers

A physical map of the GLC1A region was constructed
integrating data from our YAC contig [Belmouden et
al., 1997] and from a BAC contig (unpublished data)
(Fig. 1). The new microsatellite markers NGA8,
NGA11, NGA12, NGA13, NGA14, NGA15, NGA17,
and NGA19 were recently described and typed as previously described [Adam et al., 1997].
Linkage Analysis
Pedigree data were exported for linkage analysis
with FASTLINK software version 3.0 [Lathrop and
Lalouel, 1984; Cottingham et al., 1993]. A dominant
model was adopted. A frequency of 0.0001 was taken
for the GLC1A gene. To account for the variable age of
onset (see Results and Fig. 3), five liability classes were
defined. Class 1 included subjects < 21 years of age;
class 2, 2129; class 3, 3042; class 4, 4249; class 5, >
49 years of age. The penetrance values of the disease
allele were 0.25, 0.50, 0.75 for class 1 to 3, respectively,
and 0.95 for class 4 and 5. These values were obtained
by plotting the penetrance distribution function, yielding the cumulative proportion of affected subjects as a
function of age at the time of diagnosis, using the
Kaplan-Meier product-limit estimator (see Fig. 3). The
phenocopy rates allowed were 0.0001 for classes 13,
0.001 for class 4, and 0.01 for class 5. Allele frequencies
of microsatellite markers were determined by typing a
cohort of 105 spouses from our family set.
Ages at the time of examination were compared
among groups with the U-test of Mann-Whitney.
Mutation Analysis
Sequencing of the GLC1A gene was carried out as
previously described [Adam et al., 1997]. For rapid mutation detection, PCR products were dot-blotted on a

Fig. 1. Map of the GLC1A region and disease-associated haplotypes. A: Physical map of the GLC1A region integrating data from a YAC contig
[Belmouden et al., 1997] and from a BAC contig (our unpublished data). The markers at the top were positioned approximately in the indicated intervals
by STS-content analysis of BACs. Grouped markers were not dissociated by recombination events or by STS analysis. Polymorphic markers are printed
in boldface. B: Extent of the disease-associated GLC1A haplotypes shared by Families 1, 2, 10, and 19 (top), 27 (middle), and 14 (bottom).

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Brezin et al.

nylon membrane and hybridized with a 17-mer oligonucleotide probe matching either the wild type or the
mutated sequence. Filters were washed to obtain a sequence-specific signal.
RESULTS
Clinical Findings
Six families of unequal size were studied (Fig. 2). The
largest one (Family 1) extended over 9 generations and
included 62 glaucomatous or reportedly blind patients,
of whom 40 were alive. The second largest family (Family 2) comprised 7 generations and 19 glaucomatous
patients, of whom 10 were alive at the time of the
study. The other four families (10, 14, 19, and 27) were
of much smaller size and included 3, 6, 4, and 8 participating patients, respectively. Altogether 205 individuals were contacted and accepted to participate in
this study (132, 31, 15, 9, 6, and 12 for Families 1, 2, 10,
14, 19, and 27 respectively). Most members of these
families were living in Northern France, in the Departments of Nord and Pas-de-Calais for Families 1, 2, and
10, in the Paris area for Family 19, and in Normandy
for Families 14 and 27. Ancestors of four of these families (1, 2, 10, and 19) were identified in a limited area
delineated by Boulogne-sur-mer, Calais, and SaintOmer, in the Pas-de-Calais.
In these six families, POAG was associated with a
normal iridocorneal angle. Peak IOP was elevated but
varied widely, between 22 and 50 mmHg and above.
Filtration surgery was performed in 93/140 eyes. Age
at diagnosis was also variable and ranged between 10
and 65 years. Figure 3 shows the penetrance curve as a
function of age at diagnosis. Twenty-five, 50, and 75%
of the cases were recognized at the age of 21, 30, and 42
years, respectively. When families were analyzed separately, both juvenile-onset and middle-age onset cases
were seen in Families 1, 2, 14, and 27, whereas POAG
was of the juvenile-onset type in Family 19 (age at
diagnosis ranging between 21 and 28 years) and of the
adult type in Family 10 (40, 40, and 50 years for the 3
patients of this family, respectively).
GLC1A Linkage and Mutation Analysis
Segregation analysis of POAG in Family 1, which
has been almost completely ascertained, was consistent with an autosomal dominant monogenic mode of
inheritance and a high penetrance rate. Fifty-two of
107 children (48.6%) having an affected parent were
glaucomatous. The transmitting parent was the
mother in 17 cases and the father in 16 cases. A similar
analysis could not be performed on Family 2, which has
been characterized only partially, whereas the size of
the other four families was too small to allow firm conclusions.
Linkage of POAG to the GLC1A region was tested in
these families using microsatellite markers spanning
the GLC1A region (Fig. 1). Two-point lod score data for
three of these markers are shown in Table I. These
data strongly support linkage to GLC1A (maximum lod
scores of 24.2, 29.7, and 32.5 for D1S2851, NGA1, and
D1S218, respectively).
Sequencing of the GLC1A gene using PCR-amplified

genomic DNA samples from representative glaucomatous patients belonging to Family 1, 14, and 27 had
identified a C to A transversion at position 1440 [Adam
et al., 1997]. This mutation changed an Asn into a Lys
at residue 480 (N480K). It was also present in Families
2, 10, and 19. A dot-blot assay of PCR-amplified genomic DNA followed by hybridization with oligonucleotide probes matching either the mutated or the wild
type sequence was then set up to facilitate the screening of mutation carriers (Fig. 4). The N480K mutation
was carried by all patients of the six families whereas
it was not detected among 150 unrelated controls.
These findings indicated that the N480K substitution
was responsible for the disease in these pedigrees.
Haplotype Analysis and Founding Effect
To discriminate between a founder effect and a de
novo recurrence, disease-associated haplotypes across
the GLC1A region were determined by typing 26 microsatellite markers covering 8 cM (Fig. 1A). This demonstrated that mutation N480K was associated with a
common haplotype including the 26 markers in families 1, 2, 10, and 19 (P < 1016). Seven of these 26
markers were particularly informative due to the low
frequencies of their disease-associated alleles in the
general population (0.067, 0.072, 0.133, 0.045, 0.0053,
0.121, and 0.033 for NGA1, D1S2851, AFM21, NGA13,
D1S1165, D1S2790, and D1S218, respectively) (P <
108). Part of this extended haplotype was identified in
association with the N480K mutation in Families 14
and 27 (Fig. 1B). It included NGA15 and markers distal
to it in Family 27 (P < 1012) and markers from NGA14
to AFM107yg1 in Family 14 (P < 105).
Two groups of POAG-unrelated patients were then
screened for the presence of the N480K mutation. The
first one included 67 Caucasian patients with POAG
originating from Northern France and who had undergone trabeculectomy before the age of 50. This selection
bias was intended to favor the founder effect associated
with the N480K mutation in Northern France and to
increase the odds of identifying carriers of this mutation. The second group included 56 consecutive POAG
patients who consulted at the Glaucoma Institute of
the Saint-Joseph Hospital in Paris. Only one patient
from the first group was found to carry the N480K
mutation. This patient harbored the extended haplotype of Families 1, 2, 10, and 19, and had at least four
glaucomatous first-degree relatives.
Altogether, these findings indicated that the 71 patients from Families 1, 2, 10, 14, 19, and 27 and the
patient identified by screening were all linked by a
founding effect and had inherited their mutation from
a common ancestor.
Variable Expressivity of the GLC1A Gene
The set of 71 patients described above provides a
unique opportunity for analyzing the variability of the
phenotype determined by the N480K mutation. The
age at diagnosis is one parameter of this variability. In
light of the mutation typing data, cumulated penetrance rates of the disease gene as a function of the
age of patients at diagnosis or of the age of unaffected

Fig. 2. Family trees. Filled and crossed symbols indicate POAG patients and unaffected individuals under 18 years of age, respectively. Among living subjects, those who were genotyped are marked
by a slanted T.

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Brezin et al.

Fig. 3. Age-dependent penetrance

of OAG. The proportion of remaining
unaffected subjects has been plotted
against age at the time of diagnosis.

carriers at the time of the study could then be reevaluated as follows: 25% at 19 years, 50% at 26 years, 75%
at 32 years, and >95% at 57 years.
Whereas juvenile-onset is usually associated with a
severe course of the disease, a later age at diagnosis
may be the result of either a late diagnosis or a late
onset of disease. The following three selected cases examplify three typical clinical situations encountered
among carriers of the N480K mutation.
Juvenile POAG. The daughter of a severely affected woman from Family 14 was first diagnosed with
POAG when she was 21 years old. Her peak IOP was

then 28 mmHg OU. Treatment was initiated by a topical beta-blocker alone, then in combination with pilocarpine. Filtrating surgery was perfomed on both eyes
1 year later. Now, at the age of 23, her current IOP is
OD: 15 mmHg, OS: 12 mmHg. Her optic discs are excavated, with a cup/disk ratio of 0.8. Her visual fields
show severe defects (Fig. 5A).
Middle-age POAG. A 52-year-old woman from
Family 1 with previously normal ophthalmic examinations was genotyped. She carried the diseaseassociated haplotype of her family and the N480K
GLC1A mutation. Recently, her IOP was measured at

TABLE I. Two-Point Lod Scores for OAG and GLC1A-Linked Microsatellite Markers
Recombination fraction
Marker

Family

D1S2851
1
2
10
19
14
27
NGA1
1
2
10
19
14
27
D1S218
1
2
10
19
14
27

0.0

0.01

0.05

0.1

0.2

0.3

0.4

Zmax

Theta (%)

23.84
14.93
5.05
1.19
0.47
1.34
0.86
29.36
18.62
6.00
1.21
0.81
1.26
1.46
27.57
16.16
6.33
1.25
0.85
1.34
1.64

24.21
15.50
4.94
1.17
0.45
1.31
0.84
29.65
19.06
5.94
1.18
0.80
1.24
1.43
32.49
21.28
6.24
1.22
0.83
1.32
1.60

22.91
14.99
4.51
1.05
0.40
1.20
0.76
28.17
18.36
5.59
1.06
0.73
1.13
1.30
30.99
20.59
5.86
1.10
0.77
1.20
1.47

20.54
13.67
3.94
0.90
0.34
1.05
0.64
25.50
16.79
5.04
0.91
0.64
0.98
1.14
28.19
18.90
5.32
0.95
0.68
1.05
1.29

15.20
10.42
2.78
0.61
0.23
0.74
0.42
19.31
12.99
3.75
0.61
0.47
0.69
0.80
21.64
14.74
4.08
0.64
0.50
0.75
0.93

9.54
6.78
1.63
0.34
0.13
0.44
0.22
12.54
8.68
2.34
0.33
0.30
0.42
0.47
14.35
9.96
2.69
0.36
0.32
0.46
0.56

4.21
3.10
0.66
0.14
0.06
0.19
0.06
5.74
4.12
1.00
0.12
0.14
0.18
0.18
6.80
4.83
1.26
0.14
0.15
0.20
0.22

24.2

0.8

29.7

0.7

32.5

0.9

Founder Effect in Familial POAG

443

Fig. 4. N480K mutation detection by dot-blot hybridization with indicated sequence-specific oligonucleotide probes of PCR-amplified genomic
DNA from a noncarrier (lane 1) and a carrier (lane 2), verified by nucleotide sequencing. Lane 3: no DNA.

different time-points and peak IOPs of OD: 19 mmHg,

OS: 23 mmHg were observed. She had no obvious sign
of optic disc cupping. Two consecutive visual field tests
showed early defects (Fig. 5B). After 6 months of treatment by a topical beta-blocker, her IOP was found to be
elevated (OD: 16 mmHg; OS: 27 mmHg). She is currently scheduled for filtrating surgery.
Unaffected mutation carrier. A 46-year-old
woman from Family 1 was found to carry the diseaseassociated haplotype of her family and the N480K
GLC1A mutation. Repeated IOP measurements (6
time-points from 6 AM to 9 PM) were all equal to or
below 13 mmHg OU. Her optic discs had a normal appearance. Results of visual field testing with the Humphrey perimeter (24-2) were normal.

Fig. 6. Histograms of ages of POAG patients at diagnosis (hatched

bars), unaffected carriers (closed bars), and noncarriers (open bars) of the
N480K mutation at the time of the study.

Unaffected Carriers of the N480K Mutation

Mutation screening led to identify 14 unaffected carriers of the N480K mutation. These individuals had a
normal IOP on two measurements. Ophthalmoscopy
showed a normal optic disc and the visual field was not
altered. The third selected case just described represented an extreme case of nonpenetrance of the disease
gene at the age of 46. The other 13 carriers were under 32 years of age. Analysis of their age distribution
(Fig. 6) indicated that they were slightly younger than
POAG patients at the time of diagnosis (P 4 0.02). This
suggests that these individuals were at high risk of
developing glaucoma in the short term. In contrast,
these two groups were very significantly younger than
the noncarriers (P 4 1 104 for POAG patients and P
4 6 106 for unaffected carriers) as expected from the
proportion of early-onset POAG cases (75% of cases diagnosed under 40 years of age).
DISCUSSION

Fig. 5. Visual fields in selected cases. A: Juvenile POAG. 30 visual

field testing with the Octopus 101TM perimeter. Bilateral visual field defect, with a more advanced scotoma in the right eye. B: Middle-age POAG.
30 visual field testing with the HumphreyTM perimeter. Early defects
were observed in both eyes. On these grayscale printouts, visual function
varies inversely with darkness.

The 6 families described in this study provide the

first documented example of a founding effect in
POAG. They represent the largest group of patients
carrying the same mutation of the GLC1A gene. The
relationship between four of these families (1, 2, 10,
and 19) had been recognized by haplotype analysis before the molecular characterization of the GLC1A gene.
In contrast, it was the finding of the same N480K mutation in Families 14 and 27 as in Family 1 [Adam et
al., 1997] that led us to compare their diseaseassociated haplotype to that of Family 1 and thus to
establish their common ancestry.
The N480K mutation, as all mutations described to
date, maps to the third exon of the GLC1A gene [Adam
et al., 1997]. This exon encodes a 260 amino acid domain that is significantly conserved throughout evolution, from mammals to amphibians and nematodes. We
proposed to designate this domain as the olfactomedinhomology domain since bullfrog olfactomedin was the
first described member of this novel protein family

444

Brezin et al.

[Yokoe and Anholt, 1993]. Olfactomedin is a major

structural component of the chemosensory surface of
the olfactory epithelium. It is synthesized in very large
quantities by sustentacular cells and by acinar cells of
Bowmans glands and then exported into the deep mucous layer of the extracellular matrix of the olfactory
epithelium. In contrast, little is presently known about
the GLC1A gene product. However, the evolutionary
conservation of the C-terminal olfactomedin homology
domain and the concentration of the POAG-associated
mutations at its level suggests that it plays an essential, yet unknown, physiological role. Remarkably, the
mutation reported in this study substitutes a lysine to
an asparagine that remains unchanged in the four prototypic members of the olfactomedin family including
TIGR [Stone et al., 1997], bullfrog olfactomedin (OLF)
[Yokoe and Anholt, 1993], mammalian brain olfactomedin-related proteins (rNORP and hNORP) [Danielson
et al., 1994] and the F11C3.2 predicted protein from
Caenorhabditis elegans. Furthermore, this asparagine
belongs to a conserved 12-aminoacid motif (Fig. 7).
Study of the N480K mutation should therefore provide
most useful information on the structure-function relationship of the GLC1A gene product.
Haplotype analysis indicated that the N480K mutation was inherited from a common founder. Four of the
6 families had identified ancestors in the Boulonnais
area, between Boulogne-sur-Mer, Saint-Omer, and
Calais. An extensive genealogical investigation has allowed further reconstitution of the trees of Family 1
and Family 2 and the identification of 6 and 3 additional generations, respectively (data not shown). However, we were not able to interconnect the pedigrees.
The six families characterized in this study probably
represent but a few branches of the tree that stems
from the founder. Indeed, some of these branches, notably in Family 1, now reside all over France and overseas, resulting in the spreading of the mutation. We
have observed a similar, though more limited, founder
effect, with a different mutation, Ile499Phe, in two
families from Western France grouping 13 patients.
However, recurrence of mutations can also result from
independent occurrences and not from a founder effect.
This is the case of the Pro370Leu mutation, which has
been identified in two distinct families as shown by
analysis of their disease-associated haplotypes [Adam
et al., 1997]. Despite the recurrence of 3 mutations in
French POAG families, screening of 67 patients from
Northern France having undergone trabeculectomy be-

Fig. 7. Evolutionary conservation of the mutated asparagine at position

480 and of the surrounding residues in the olfactomedin family. OLF: olfactomedin (bullfrog); hNORP and rNORP: human and rat neuronal olfactomedin-related protein, respectively; F11C3.2: predicted protein from C.
elegans. Identical residues and conservative changes in four or more of the
sequences are shaded and boxed, respectively.

fore the age of 50 disclosed only one case of the N480K

mutation. In fact, besides this exception, none of the
other mutations known in French GLC1A-linked
POAG families was detected in this group of patients
nor in 56 additional unselected POAG patients. In their
seminal work, Stone et al. [1997] observed the
Gln368Stop mutation in 2.9% of 103 unselected patients. This suggests that recurrence of mutations is
not the rule and that either there is a diversity of
GLC1A mutations or GLC1A mutations account for a
minority of POAG cases or both. Characterization of
this diversity will be nevertheless essential to design
an optimal mutation screening strategy.
This report confirms that the range of phenotypes of
GLC1A-linked disease includes both juvenile and
middle-age onset POAG. Our observation of a 52-yearold woman at the beginning of her disease shows conclusively that late-onset cases are not artefacts due to
a late diagnosis of glaucoma. Factors influencing the
age of onset of POAG among our patients remain unknown. Interestingly, a preliminary analysis suggests
that cases of similar severity could be clustered in a
given family branch, which would favor a role for genetic factors. Modifier genes influencing the clinical
profile of some human diseases including late-onset familial Alzheimers disease [Corder et al., 1993], psoriasis vulgaris [Schmitt-Egenolf et al., 1996], type I diabetes [Mizota et al., 1996], and familial adenomatous
polyposis [Dobbie et al., 1997] have been described. The
knowledge of similar factors in familial POAG would be
most useful, in particular for anticipating the onset of
the disease in unaffected carriers and for adjusting
their follow-up and their therapeutic management.
Compared to other GLC1A mutations, the N480K
mutation is of intermediate severity. For instance, all
but one of the carriers of the above-mentioned
Pro370Leu mutation were diagnosed with glaucoma
before the age of 17 [Adam et al., 1997]. The remaining
patient was 27 at the time of diagnosis but had severely
altered visual fields, providing an example of late diagnosis. Conversely, less deleterious mutations of
GLC1A might be responsible for milder forms of POAG
with later onset. The ongoing assessment of the various
GLC1A mutations will help determine whether they
reproducibly correlate with expressivity.
We have previously shown that GLC1A-linkage was
a significant risk factor for developing glaucoma and
severe glaucomatous optic neuropathy in POAG families [Brezin et al., 1997]. So far, cases of isolated ocular
hypertension have been reported in only two families
with a GLC1A mutation. As in our previous reports of
GLC1A-linked glaucomas, isolated ocular hypertension
was not seen in patients with the N480K mutation.
This may be explained either by the simultaneous onset of IOP increase and optic neuropathy or by a very
short time interval between these two events. Only the
long-term prospective follow-up of unaffected mutation
carriers will allow us to characterize the earliest signs
of the disease. By identifying 14 unaffected carriers of
the N480K mutation, our study provides the means of
addressing this issue. The optimal follow-up of these
individuals at high risk of developing glaucoma remains to be codified, hopefully in light of the knowledge

Founder Effect in Familial POAG

of the factors influencing the expressivity of GLC1A

mutations. Given the availability of treatments that
efficiently prevent visual field loss, identifying these
at-risk individuals should become a public health concern.
ACKNOWLEDGMENTS
We are most grateful to Mrs Cathy Beauvais for expert technical assistance, to Dr. Delepine for giving us
access to his records, and to the families for their cooperation. This work was supported by funds from INSERM, Association pour la Recherche en Genetique
Ophtalmologique, GREG-genome, and Mutuelle Generale de lEducation Nationale. A.P.B and M.F.A were
fellows of the Fondation pour la Recherche Medicale.
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