Open Journal of Ophthalmology, 2012, 2, 64-70
http://dx.doi.org/10.4236/ojoph.2012.23014 Published Online August 2012 (http://www.SciRP.org/journal/ojoph)
Investigation of Four Genes Responsible for Autosomal
Recessive Congenital Cataract and Highly Expressed in the
Brain in Four Unrelated Tunisian Families
Manèl Chograni1, Myriam Chaabouni1,2, Faouzi Maazoul2, Habiba Chaabouni Bouhamed1,2*
1Laboratoire de Génétique Humaine, Faculté de Médecine de Tunis, University Tunis Elmanar, Tunis, Tunisia; 2Congenital and
Hereditary Disorders Department, Charles Nicolle Hospital, Tunis, Tunisia.
Received March 14th, 2012; revised April 28th, 2012; accepted May 11th, 2012
ABSTRACT
Purpose: To identify the causative gene for phenotypes associating autosomal recessive congenital cataract, mental re-
tardation and congenital cataract, mental retardation and microcephaly in four unrelated Tunisian families. Methods:
Four genes (EPHA2, GALK1, GCNT2, and CRYBB1) were selected based on their expression in human brain and their
known or putative function. Linkage analysis were performed for the four genes in multiple affected and unaffected
families’ members and results were explored by the GeneMapper ID v3.2 software. Results: No linkage was identified
for the four studied genes in the four families. Affected members of each family did not share common haplotypes in
corresponding candidate regions containing selected gene. Conclusion: Although the four studied genes were reported
responsible for autosomal recessive congenital cataract and highly expressed in the human brain, we report no linkage
for EPHA 2, GALK1, GCNT2, and CRYBB1 genes in four families with congenital cataract, mental retardation and con-
genital cataract, mental retardation and microcephaly.
Keywords: Congenital Cataract; Mental Retardation; Microcephaly; Autosomal Recessive; Association; Linkage Study
1. Introduction
Congenital cataracts are one of the major causes of vision
loss in children worldwide and are responsible for ap-
proximately one third of blindness in infants [1]. Con-
genital cataracts can occur in an isolated fashion or as
one component of a syndrome affecting multiple tissues.
Nonsyndromic congenital cataracts have an estimated
frequency of 1 to 6 per 10,000 live births. They vary
markedly in severity and morphology, affecting the nu-
clear, cortical, polar, or subcapsular parts of the lens or,
in severe cases, the entire lens, with a variety of types of
opacity. Approximately one third of congenital cataract
cases are familial [2].
Few autosomal recessive cataract loci have been mapped.
To date, 13 loci residing on chromosomes 1p34.4-p32.2,
1q21.1, 3p22-24.2, 6p23-24, 9q13-22, 16q21-22, 19q13,
19q13.4, 20p12.1, 21q22.3, 22q11, 22q12.1 and 17q,
have been mapped, with six of these also causing auto-
somal dominant cataracts [3-12].
EPHA2 (Ephrin-receptor type-A2) belongs to the tyro-
sine kinase family of proteins and is an epithelial cell ki-
nase that has been associated with autosomal dominant
cataracts and recently it was implicated in ARCC in hu-
man [11]. EPHA2 is expressed in a variety of different
regions during development. Expression has been ob-
served in the hindbrain, specifically in rhombomere 4,
during early embryogenesis [13].
Galactokinase (GALK1) is involved in the first step of
metabolism of galactose, the conversion of galactose to
galactose-1-phosphate at the expense of ATP. In the ab-
sence of GALK1 the accumulating galactose is converted
to galactitol by aldose reductase. Stambolian and col-
leagues first identified mutations in families with cata-
racts [14]. And recently GALK1 found to be mutated in
Pakistani families with ARCC [12].
Glucosaminyl (N-acetyl) Transferase 2 Gene (GCNT2)
had been reported for ARCC in Arab families from Israel
[4]. GCNT2 is highly expressed in fetal brain and kidney
and adult brain but expressed ubiquitously in various
adult tissues [15].
Crystallin genes, which encode major structural pro-
teins in the lens, are considered as obvious candidate ge-
nes of congenital cataracts owing to both their high levels
of lenticular expression and their confirmed functions in
maintaining lens transparency. Increasing evidence sug-
*Corresponding author.

Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly
Expressed in the Brain in Four Unrelated Tunisian Families
65
gests the correlated relationship between mutations in the
crystallin genes with the occurrence of congenital cata-
racts in humans [16]. βB1-crystallin gene (CRYBB1) mu-
tations have been shown to underlie autosomal dominant
congenital cataract [17]. To date, two reports had under-
lined CRYBB1 mutations associated with ARCC [10].
This report describes the investigation of four posi-
tional and functional candidate genes of autosomal re-
cessive congenital cataract (ARCC) for phenotypes asso-
ciating ARCC, mental retardation (MR) and ARCC, MR,
and microcephaly. The genes were chosen on the basis of
lens and human brain expression.
2. Methods
2.1. Subjects and Sample Collection
We evaluated fifteen patients (6 parents, 9 patients) be-
longing to four unrelated Tunisian families (Figure 1)
addressed to Congenital and Hereditary Disorders De-
partment at Charles-Nicolle Hospital (Tunis, Tunisia).
All four families were of Tunisian origin and were en-
rolled in a genetic research program in the laboratory of
Human Genetics, in the Faculty of Medicine (Tunis, Tu-
nisia) because of four patients with ARCC and MR (two
affected brothers belonging to family F2 and two patients
of family F4) and five affected patients from families F1,
F2, and F3 with ARCC, MR and microcephaly.
The nine patients (5 males, 4 females) were born from
healthy and consanguineous parents. Pedigrees’ patterns
are concordant with autosomal recessive inheritance for
the four families (Figure 1). Their mean age was 23 years,
ranging from 8 to 41 years. We noted that the father from
family F1 was dead after a traumatic accident and the
other from family F4 lived abroad. Cataracts were re-
portedly present since birth in all patients. None had
glaucoma before or after the extraction of cataracts.
The cataracts were of the posterior polar type and bi-
lateral in all patients except of the affected children IV12
belonging to family F3 and IV13 from family F1. All pa-
tients had undergone cataract extraction early in life.
Visual acuity was preserved in all patients except of the
affected patients IV11 from family F3 who showed de-
creased visual acuity and alteration of the pigment epi-
thelium. We denoted the presence of retinal dystrophy
and strabismus in patient IV16 belonging to family F1.
We underlined also the presence of strabismus (exotropia)
in patient III16 from family F4.
Significant physical disability became apparent for all
patients by the age of 15 to 18 months when they failed
to walk. They also had a significant delay in speech de-
velopment. In fact, the nine affected patients were de-
velopmentally delayed with mild to moderate mental re-
tardation with no dysmorphic features. Microcephaly,
suspected since birth, was present in all of them except
the two brothers IV36 and IV37 belonging to family F2
and the two patients from family F4. Additional features
are shown in Table 1.
Congenital cataract + Mental retardation + Microcephaly
Congenital cataract + Mental retardation
Mental retardation/Not examined
Late-onset cataract/Not examined
Figure 1. Pedigrees of the four studied families: F1, F2, F3, and F4 showing autosomal recessive inheritance of the congenital
cataract. The asterisk indicates not examined.

Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly
Expressed in the Brain in Four Unrelated Tunisian Families
66

Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly
Expressed in the Brain in Four Unrelated Tunisian Families
67
Magnetic resonance imaging (MRI) of the brain was
normal in all screened patients except for the presence of
a small ischemic parietal lesion in patient IV16 from fam-
ily F1.
Biological investigations (karyotyping with R-banding)
revealed normal karyotypes: 46, XX for females, 46, XY
for males (600 bands resolution) and normal metabolic
screening including Fehling reaction and thin layer chro-
matography of reducing sugars, plasmatic amino acid
and urine organic acid chromatography for all patients.
Genomic DNA of affected and unaffected members (9
siblings, 6 parents) was extracted from peripheral blood
leukocytes by the standard proteinase-K extraction con-
sisting on: lysis of red blood cells by RBC (Red Blood
Cells) Lysis Buffer (155 mM NH4Cl, 10 mM KHCO3,
0.5 EDTA, pH 7.5) and white blood cells by a WBC
(White Blood Cells) Lysis Buffer (1 mM Na-EDTA,
5mM Tris HCl, pH 7.5), treatment of the lysate with a
mixture of detergent composed of SDS (Sodium Dodecyl
Sulfate or sacrosyl and proteinase K) in order to liberate
the DNA and digest the associated proteins, precipitation
of the DNA in the form of filaments by absolute ethanol
and finally diluation of the DNA in T10E1 Buffer (Tris
10 mM, EDTA 0.1-1 mM), and stored in 10 ml Vacuum
tube sterile containing 100 µl of 0.1 M EDTA.K3.
Patients and parents for minors gave informed consent.
In this study, the researches carried out on human are in
compliance with the Helsinki Declaration and ethics com-
mittee Charles Nicolle hospital, Tunis has given approval
for this study.
2.2. Molecular and Genotyping Analysis
On the basis of the pedigree of the four studied families
(Figure 1), we suspected autosomal recessive inheritance
for phenotypes associating congenital cataract, mental re-
tardation and congenital cataract, mental retardation, and
microcephaly.
All individuals were genotyped for eight microsatellite
loci within a 10-cM region on 1p36.21-p35.2 previously
reported as linked to EPHA2 (D1S2697-D1S1592-D1
S2644-D1S2864-D1S2787-D1S507-D1S434-D1S2667)
[11,13], at six microsatellite loci on 17q22-q25.3 linked
to GALK1 (D17S944-D17S1825-D17S1301-D17S1839-
D17S785-D17S1847) [12], at five microsatellite loci on
6p25-p23 reported as linked to GCNT2 (D6S1574-D6
S309-D6S470-D6S1034-D6S289) [4], and at six micro-
satellite loci on 22q11.2-q12.1 previously reported as
linked to CRYBB1 (D22S539-D22S686-D22S345-D22
S419-D22S1167-D22S1144) [10].
Suitable microsatellite primers for polymerase chain
reaction (PCR) amplification of each candidate region
containing the candidate gene were designed using NCBI
(http://www.ncbi.nlm.nih.gov/unists).
PCR was performed by using 100 ng of DNA template,
20 pmol each of forward (FAM labelled) and reverse
primers (Biomatik, Canada), 1.5 units of Taq DNA poly-
merase (Promega, Madison, WI) and 1.25 mM dNTPs
(Promega, Madison, WI) in a total volume of 25 μl. PCR
consisted on 30 cycles and was carried out in an auto-
mated thermal cycle GeneAmp PCR System 9700 (Ap-
plied Biosystems, California) under the following condi-
tions: initial denaturation at 96˚C for 5 min and denatura-
tion at 96˚C for 30 s, annealing at 52˚C - 60˚C for 30 s,
and elongation at 72˚C for 30 s followed by one cycle of
final extension at 72˚C for 7 min. Genotyping was per-
formed on a genetic analyser (PRISM 3130; ABI) with
accompanying software (GeneScan; ABI, Foster City,
CA).
2.3. Linkage Analysis
Two-point LOD scores were calculated using the MLINK
program of the LINKAGE package (ver. 4.1P;
http:www.hgmp.mrc.ac.uk; provided in the public do-
main by the Human Genome Mapping Project Resources
Centre, Cambridge, UK), and multipoint and haplotype
analyses were performed with GeneMapper ID v3.2 soft-
ware.
3. Results
Segregation analysis using the polymorphic markers on
chromosome 1 for EPHA2, on chromosome 17 for GALK1,
on chromosome 6 for GCNT2 and on chromosome 22 for
CRYBB1 within minimum 10-cM region allowed us to
exclude implication in studied phenotypes (congenital
cataract, mental retardation and congenital cataract, men-
tal retardation, and microcephaly) of all regions analyzed
seeing that the affected members and their parents did
not share a common haplotype.
There is no linkage of anyone of the four genes
(EPHA2, GALK1, GCNT2, and CRYBB1) to the associa-
tion between ARCC, MR and ARCC, MR, and micro-
cephaly in the four studied families (F1, F2, F3, and F4).
4. Discussion
Congenital cataracts are common major abnormalities of
the eye, which frequently cause blindness in infants. It
may occur as an isolated anomaly, as part of generalized
ocular development defects, or as a component of a mul-
tisystem disorder [18]. In fact, association of cataract
with congenital anomalies, mental retardation and micro-
cephaly is reported in several cases with chromosomal
anomalies and syndromes from genic origins [19-21].
Until today no candidate gene has been reported re-
sponsible for phenotypes associating ARCC, MR and
ARCC, MR, and microcephaly, so we tried to investigate

Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly
Expressed in the Brain in Four Unrelated Tunisian Families
68
genes already described in ARCC and highly expressed
in the human brain particularly during embryogenesis
(EPHA2, GALK1, GCNT2, and CRYBB1).
EPHA2 belongs to the tyrosine kinase family, and the
protein EphA2 is an epithelial cell kinase that interacts
with membrane-bound ephrin ligands, which play an
important role in morphogenesis and in numerous de-
velopmental processes [22]. For the first time, it was re-
ported responsible for autosomal dominant cataracts
(ADCC) and recently it was implicated in age-related
cortical cataracts in humans and mice [14,23]. In 2010,
Kaul et al. reported the first missense mutation leading to
an ARCC in a consanguineous Pakistani family [11].
EPHA2 is transcribed abundantly in tissues or cells of
epithelial origin, although the expression is not limited to
epithelial cells. EPHA2 is expressed in a variety of dif-
ferent regions during development [13,14]. Expression
has been observed in the distal region of the primitive
streak and in the hindbrain, specifically in rhombomere 4,
during early embryogenesis. Later in development, ex-
pression is detected in the branchial arches, neurogenic
facial crest VII-VIII and IX-X, and in the limb bud mes-
enchyme. In the central nervous system, EPHA2 is widely
transcribed in the ventricular zone cells in midgestation [14].
GALK1 is involved in the first step of metabolism of
galactose, the conversion of galactose to galactose-1-pho-
sphate at the expense of ATP. In the absence of GALK1
the accumulating galactose is converted to galactitol by
aldose reductase. Stambolian and colleagues first identified
mutations in GALK1 in families with cataracts [12]. Re-
cently, Yasmeen and coworkers reported a missense mu-
tation and a single base pair deletion leading to ARCC in
a consanguineous Pakistani family. GALK1 found to be
highly expressed in many human organs from foetuses to
adults; brain, heart, kidney, liver, lung, muscle and spleen
[24].
For GCNT2 three splicing variants GCNT2A, -B, and
-C, which differ at exon 1 but have identical exon 2 and 3
coding regions, are expressed differentially in specific
tissues. Mutation events that occur in the specific exon 1
region of the GCNT2 gene may lead to a defect in one
form of the GCNT2 enzyme and I phenotype in certain
cell types, whereas those that occur in the common exon
2 to 3 region result in i phenotype as well as congenital
cataract, because of the elimination of activity of all three
forms of the GCNT2 enzymes [25]. Pras and colleagues
reported four distantly related Arab families from Isreal
with a nonsense mutation in the GCNT2 gene isoforms
associated to ARCC [4].
GCNT2 isoforms are abundantly expressed in various
none rythroid tissues. In fetal tissues, GCNT2 was subs-
tantially expressed in brain and moderately expressed in
kidney and lung but was almost undetectable in liver. In
adult tissue, GCNT2 was strongest in prostate, moderate
in small intestine and colon, and barely detected in heart,
brain, kidney, and pancreas. In adult brain, GCNT2 is
much more prominent in cerebellum than the other parts
of brain [15].
Crystallins (α-crystallin family and the β/γ-crystallin
superfamily) are highly stable major constituents of the
vertebrate eye lens and comprise approximately 90% of
the water-soluble lens proteins. They have a particular
spatial arrangement critical to the transparency of the
lens and are hence good candidate genes for congenital
cataract disease [26]. To our knowledge, there are only
six previous reports of CRYBB1 mutations in patients
with congenital cataract and only two of these in patients
with autosomal recessive cataract [10,17]. β-crystallins
are expressed from early developmental stages in the eye
lens, their expression continues and rises after birth so
that the highest concentrations are usually found in the
lens cortex.
Taking these results further, we tried to investigate the
existence of a possible association between one or more
of these genes (EPHA2, GALK1, GCNT2, and CRYBB1)
and studied phenotypes in the four Tunisian families
(ARCC, MR and ARCC, MR, and microcephaly). No
linkage was detected in the four genotyped candidate re-
gions containing each gene for the four studied families.
These findings did not exclude the role of EPHA2, GALK1,
GCNT2, and CRYBB1 genes in both ocular and central
nervous system but it underlined the fact that none of
these genes could be responsible for the association between
congenital cataract, mental retardation and congenital
cataract, mental retardation, and microcephaly (suspected
since birth in all examined patients) in these families.
In conclusion, a genome wide scan must be performed
for these four families in order to identify candidate re-
gions and candidate gene(s) leading to the unreported as-
sociations between ARCC, MR and ARCC, MR, micro-
cephaly.
5. Acknowledgments, Competing In ter est s
The authors thank all the patients and their family mem-
bers for participating in the project. This study was sup-
ported by Laboratory of Human Genetics, Faculté de
Médecine de Tunis, Ministry of Higher Education and
Scientific Research and Technology and by Congenital
and Hereditary Service of Charles Nicolle’s Hospital in
Tunisia.
The authors of the manuscript declare that they have
no competing interests.
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