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

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Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly Expressed in the Brain in Four Unrelated Tunisian Families 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. Email: *[email protected] 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 EPHA2, 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 cataracts and recently it was implicated in ARCC in hu- man [11]. EPHA2 is expressed in a variety of different Congenital cataracts are one of the major causes of vision loss in children worldwide and are responsible for ap- regions during development. Expression has been ob- proximately one third of blindness in infants [1]. Con- served in the hindbrain, specifically in rhombomere 4, genital cataracts can occur in an isolated fashion or as during early embryogenesis [13]. one component of a syndrome affecting multiple tissues. Galactokinase (GALK1) is involved in the first step of Nonsyndromic congenital cataracts have an estimated metabolism of galactose, the conversion of galactose to frequency of 1 to 6 per 10,000 live births. They vary galactose-1-phosphate at the expense of ATP. In the ab- markedly in severity and morphology, affecting the nu- sence of GALK1 the accumulating galactose is converted clear, cortical, polar, or subcapsular parts of the lens or, to galactitol by aldose reductase. Stambolian and col- in severe cases, the entire lens, with a variety of types of leagues first identified mutations in families with cata- opacity. Approximately one third of congenital cataract racts [14]. And recently GALK1 found to be mutated in cases are familial [2]. Pakistani families with ARCC [12]. Few autosomal recessive cataract loci have been mapped. Glucosaminyl (N-acetyl) Transferase 2 Gene (GCNT2) To date, 13 loci residing on chromosomes 1p34.4-p32.2, had been reported for ARCC in Arab families from Israel 1q21.1, 3p22-24.2, 6p23-24, 9q13-22, 16q21-22, 19q13, [4]. GCNT2 is highly expressed in fetal brain and kidney 19q13.4, 20p12.1, 21q22.3, 22q11, 22q12.1 and 17q, and adult brain but expressed ubiquitously in various have been mapped, with six of these also causing auto- adult tissues [15]. somal dominant cataracts [3-12]. Crystallin genes, which encode major structural pro- EPHA2 (Ephrin-receptor type-A2) belongs to the tyro- teins in the lens, are considered as obvious candidate ge- sine kinase family of proteins and is an epithelial cell ki- nes of congenital cataracts owing to both their high levels nase that has been associated with autosomal dominant of lenticular expression and their confirmed functions in *Corresponding author. maintaining lens transparency. Increasing evidence sug- Copyright © 2012 SciRes. OJOph Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly 65 Expressed in the Brain in Four Unrelated Tunisian Families gests the correlated relationship between mutations in the healthy and consanguineous parents. Pedigrees’ patterns crystallin genes with the occurrence of congenital cata- are concordant with autosomal recessive inheritance for racts in humans [16]. βB1-crystallin gene (CRYBB1) mu- the four families (Figure 1). Their mean age was 23 years, tations have been shown to underlie autosomal dominant ranging from 8 to 41 years. We noted that the father from congenital cataract [17]. To date, two reports had under- family F1 was dead after a traumatic accident and the lined CRYBB1 mutations associated with ARCC [10]. other from family F4 lived abroad. Cataracts were re- This report describes the investigation of four posi- portedly present since birth in all patients. None had tional and functional candidate genes of autosomal re- glaucoma before or after the extraction of cataracts. cessive congenital cataract (ARCC) for phenotypes asso- The cataracts were of the posterior polar type and bi- ciating ARCC, mental retardation (MR) and ARCC, MR, lateral in all patients except of the affected children IV12 and microcephaly. The genes were chosen on the basis of belonging to family F3 and IV13 from family F1. All pa- tients had undergone cataract extraction early in life. lens and human brain expression. Visual acuity was preserved in all patients except of the 2. Methods affected patients IV11 from family F3 who showed de- creased visual acuity and alteration of the pigment epi- 2.1. Subjects and Sample Collection thelium. We denoted the presence of retinal dystrophy and strabismus in patient IV16 belonging to family F1. We evaluated fifteen patients (6 parents, 9 patients) be- We underlined also the presence of strabismus (exotropia) longing to four unrelated Tunisian families (Figure 1) in patient III16 from family F4. addressed to Congenital and Hereditary Disorders De- Significant physical disability became apparent for all partment at Charles-Nicolle Hospital (Tunis, Tunisia). patients by the age of 15 to 18 months when they failed All four families were of Tunisian origin and were en- to walk. They also had a significant delay in speech de- rolled in a genetic research program in the laboratory of velopment. In fact, the nine affected patients were de- Human Genetics, in the Faculty of Medicine (Tunis, Tu- velopmentally delayed with mild to moderate mental re- nisia) because of four patients with ARCC and MR (two tardation with no dysmorphic features. Microcephaly, affected brothers belonging to family F2 and two patients suspected since birth, was present in all of them except of family F4) and five affected patients from families F1, the two brothers IV36 and IV37 belonging to family F2 F2, and F3 with ARCC, MR and microcephaly. and the two patients from family F4. Additional features The nine patients (5 males, 4 females) were born from 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. Copyright © 2012 SciRes. OJOph 66 Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly Expressed in the Brain in Four Unrelated Tunisian Families Copyright © 2012 SciRes. OJOph Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly 67 Expressed in the Brain in Four Unrelated Tunisian Families Magnetic resonance imaging (MRI) of the brain was PCR was performed by using 100 ng of DNA template, normal in all screened patients except for the presence of 20 pmol each of forward (FAM labelled) and reverse a small ischemic parietal lesion in patient IV16 from fam- primers (Biomatik, Canada), 1.5 units of Taq DNA poly- ily F1. merase (Promega, Madison, WI) and 1.25 mM dNTPs Biological investigations (karyotyping with R-banding) (Promega, Madison, WI) in a total volume of 25 μl. PCR revealed normal karyotypes: 46, XX for females, 46, XY consisted on 30 cycles and was carried out in an auto- for males (600 bands resolution) and normal metabolic mated thermal cycle GeneAmp PCR System 9700 (Ap- screening including Fehling reaction and thin layer chro- plied Biosystems, California) under the following condi- matography of reducing sugars, plasmatic amino acid tions: initial denaturation at 96˚C for 5 min and denatura- and urine organic acid chromatography for all patients. tion at 96˚C for 30 s, annealing at 52˚C - 60˚C for 30 s, Genomic DNA of affected and unaffected members (9 and elongation at 72˚C for 30 s followed by one cycle of siblings, 6 parents) was extracted from peripheral blood final extension at 72˚C for 7 min. Genotyping was per- leukocytes by the standard proteinase-K extraction con- formed on a genetic analyser (PRISM 3130; ABI) with sisting on: lysis of red blood cells by RBC (Red Blood accompanying software (GeneScan; ABI, Foster City, Cells) Lysis Buffer (155 mM NH4Cl, 10 mM
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