Gene Map Locus: 2p22-p21
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A number sign (#) is used with this entry because of evidence that this form of autosomal recessive primary congenital glaucoma (buphthalmos) is due to homozygosity for mutations in the cytochrome P4501B1 gene (CYP1B1; 601771).
The ocular globe is usually large as a result of the increased
intraocular pressure dating from intrauterine life, hence the term
buphthalmos, meaning 'ox eye.' In only about half of cases are both
eyes involved, and males are affected somewhat more often than
females. The canal of Schlemm is present and communicates normally
with the veins, as is proved by demonstrable filling of the canal
with blood when the jugular veins are compressed. The defect is
thought to involve the permeability of the trabeculum to aqueous
humor. Autosomal recessive inheritance is quite certain in a
significant proportion of cases. The syndrome of congenital glaucoma
with mental retardation and decreased renal ammonium production (Lowe
syndrome, 309000)
is inherited as an X-linked recessive. Autosomal recessive glaucoma
occurs in the rabbit (Hanna et al., 1962).
Bonaiti et al. (1978) concluded that about
30% of congenital glaucoma cases in the series they analyzed were of
an autosomal recessive type. In Bratislava, Czechoslovakia, Gencik
et al. (1980) studied 45 gypsy families with 118 persons with
congenital glaucoma. Inheritance was autosomal recessive with
complete penetrance. In addition, they studied 81 non-gypsy families
with 87 affected persons. Among these, 26.6% were only unilaterally
affected and onset was usually later and course milder. The
population frequency was much lower and an excess of males (1.55:1)
was noted. The authors concluded that multifactorial inheritance is
likely in the latter group. The consanguinity rate was not increased.
Demenais et al. (1981) confirmed genetic
heterogeneity of congenital glaucoma. An analysis by Morton
(1982) suggested that much etiologic heterogeneity exists in the
category of congenital glaucoma. A large gypsy pedigree with 31
affected persons in 18 sibships was reported from Slovakia by
Gencikova and Gencik (1982). Ferak
et al. (1982) published observations on the high frequency of
congenital glaucoma in a relatively small gypsy subpopulation of
Slovakia. (Plasilova et al. (1998)
performed linkage analysis on 7 Slovak gypsy (Rom) families with 18
members with congenital glaucoma and found linkage to 2p21, without
heterogeneity. This finding demonstrated that in the Rom population
of Slovakia, primary congenital glaucoma is due to locus GLC3A and
subsequently shown to be due to mutations in the P4501B1 gene
(CYP1B1; 601771).)
Using a group of 17 families with primary congenital glaucoma and
a combination of both candidate regional and general positional
mapping strategies, Sarfarazi et al.
(1995) mapped the locus, designated GLC3, to 2p. Eleven families
showed no recombination with 3 tightly-linked markers, D2S177,
D2S1346, and D2S1348, with a combined haplotype lod score of 11.50.
Haplotype and multipoint linkage analysis of 14 DNA markers from 2p
indicated to the authors that the disease gene is located in the 2p21
region and is flanked by DNA markers D2S1788/D2S1325 and D2S1356.
Inspection of haplotype and heterogeneity analysis confirmed that 6
families are not linked to the 2p21 region, thus providing the first
proof of genetic heterogeneity for this phenotype. The authors
therefore designated the locus on 2p21 GLC3A. Of 7 genes mapping to
the 2p21 region, they could exclude, on the basis of linkage
position, CAD (114010),
CALM2 (114182),
and LHCGR (152790)
as candidates for GLC3A, but mutations in PRKR (176871),
SOS1 (182530),
or SPTEN1 (182790)
could account for the phenotype.
Stoilov et al. (1997) used a
combination of GLC3A-linked polymorphic markers (STRPs), YAC
screening, and radiation hybrid mapping of published and newly
generated data on STSs and ESTs to establish a critical region that
harbors the defective gene in GLC3A . Of 5 potential candidate genes,
1 was placed outside the critical region and another 3 were screened
for the presence of coding sequence changes. As a direct result of
this screening, they identified 3 different truncating mutations in
the human cytochrome P4501B1 gene (601771).
A 13-bp deletion (601771.0001)
was detected in 1 consanguineous and 1 nonconsanguineous family; a
single cytosine insertion (601771.0002)
was observed in another 2 consanguineous families; and a large
deletion was found in an additional consanguineous family.
Victor A. McKusick - updated : 3/31/1998
Victor A. McKusick - updated : 4/28/1997
Victor A. McKusick : 6/3/1986
dkim : 12/11/1998
alopez : 3/31/1998
terry : 3/24/1998
alopez : 4/29/1997
alopez : 4/28/1997
terry : 4/22/1997
terry : 12/10/1996
mark : 9/6/1996
mark : 1/14/1996
mimadm : 2/19/1994
carol : 5/21/1993
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988