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A Arora,
P J Minogue,
X Liu, M A Reddy,
J R Ainsworth,
S S Bhattacharya,
A R Webster,
D M Hunt,
L Ebihara,
A T Moore,
E C Beyer,
V M Berthoud
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ABSTRACT: To identify the gene responsible for autosomal dominant lamellar pulverulent cataract in a four-generation British family and characterise the functional and cellular consequences of the mutation.
Linkage analysis was used to identify the disease locus. The GJA8 gene was sequenced directly. Functional behaviour and cellular trafficking of connexins were examined by expression in Xenopus oocytes and HeLa cells.
A 262C>A transition that resulted in the replacement of proline by glutamine (P88Q) in the coding region of connexin50 (Cx50) was identified. hCx50P88Q did not induce intercellular conductance and significantly inhibited gap junctional activity of co-expressed wild type hCx50 RNA in paired Xenopus oocytes. In transfected cells, immunoreactive hCx50P88Q was confined to the cytoplasm but showed a temperature sensitive localisation at gap junctional plaques.
The pulverulent cataract described in this family is associated with a novel GJA8 mutation and has a different clinical phenotype from previously described GJA8 mutants. The cataract likely results from lack of gap junction function. The lack of function was associated with improper targeting to the plasma membrane, most probably due to protein misfolding.
Journal of Medical Genetics 01/2006; 43(1):e2. · 6.36 Impact Factor
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ABSTRACT: Assess ERG responses recorded with skin electrodes in children with retinal dystrophies.
ERG responses were recorded using skin electrodes in 17 healthy children and 43 paediatric patients with retinal dystrophy. Subjects were aged 4-14 years. ERG responses were recorded to full-field stimuli similar to those recommended in the ISCEV standard. The type of retinal dystrophy was classified on the basis of standard clinical criteria and the ERG responses were compared with those of the age-matched controls.
ERG responses were abnormal in every patient. The specific type of ERG abnormality was also consistent with the clinical findings in the majority of patients. Rod responses were abnormal in every patient with a rod-cone dystrophy and cone responses were also abnormal in the majority of patients. Those patients with cone dystrophy or rod monochromatism had normal or near normal rod responses but sub-normal or absent cone responses. Patients with CSNB or XLRS had a sub-normal b-wave but normal amplitude a-wave.
ERGs can be recorded successfully with skin electrodes in paediatric patientsand responses can aid the diagnosis of the type of retinal dystrophy.
Documenta Ophthalmologica 08/2004; 109(1):57-66. · 2.11 Impact Factor
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M A Reddy,
O A Bateman,
C Chakarova,
J Ferris,
V Berry,
E Lomas,
R Sarra,
M A Smith,
A T Moore,
S S Bhattacharya,
C Slingsby
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ABSTRACT: Congenital cataract is a leading cause of visual disability in children. Inherited isolated (non-syndromic) cataract represents a significant proportion of cases and the identification of genes responsible for inherited cataract will lead to a better understanding of the mechanism of cataract formation at the molecular level both in congenital and age-related cataract. Crystallins are abundantly expressed in the developing human lens and represent excellent candidate genes for inherited cataract. A genome-wide search of a five-generation family with autosomal dominant lamellar cataract demonstrated linkage to the 17p12-q11 region. Screening of the CRYBA1/3 gene showed a 3 bp deletion, which resulted in a G91del mutation within the tyrosine corner, that co-segregated with disease and was not found in 96 normal controls. In order to understand the molecular basis of cataract formation, the mutant protein was expressed in vitro and its unfolding and refolding characteristics assessed using far-UV circular dichroism spectroscopy. Defective folding and a reduction in solubility were found. As the wild-type protein did not refold into the native conformation following unfolding, a corresponding CRYBB2 mutant was genetically engineered and its refolding characteristics analysed and compared with wild-type CRYBB2. Its biophysical properties support the hypothesis that removal of the glycine residue from the tyrosine corner impairs the folding and solubility of beta-crystallin proteins. This study represents the first comprehensive description of the biophysical consequences of a mutant beta-crystallin protein that is associated with human inherited cataract.
Human Molecular Genetics 06/2004; 13(9):945-53. · 7.64 Impact Factor
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ABSTRACT: To phenotype and genetically map the disease locus in a family presenting with autosomal dominant microcornea, rod-cone dystrophy, cataract, and posterior staphyloma.
Six affected and three unaffected members of the pedigree were examined. All individuals provided a history and underwent a full clinical examination with A-scan and B-scan ultrasonography and electrophysiological testing where appropriate. PCR based microsatellite marker genotyping using a positional candidate gene approach was then performed on DNA samples extracted from venous blood provided by each subject.
The disorder is inherited as an autosomal dominant trait with variable expressivity and has a complex phenotype. Affected individuals had bilateral microcornea, pulverulent-like lens opacities, a rod-cone dystrophy and posterior staphyloma (MRCS). Using a positional candidate gene approach, the authors have evidence suggestive of linkage of this disorder to a region on 11q13 within the nanophthalmos 1 (NNO1) genetic interval. The small family size militates against achieving a LOD score of 3, but the haplotype data and the position of the putative MRCS locus within a known nanophthalmos locus are suggestive of linkage. A candidate gene within this region (ROM1) was screened and no mutations were found in affected members of the family.
This rare developmental disorder has some phenotypic similarities to nanophthalmos and possibly maps to a locus within the genetic interval encompassing the NNO1 locus. Screening of candidate genes within this region continues.
British Journal of Ophthalmology 03/2003; 87(2):197-202. · 2.90 Impact Factor
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V Berry,
P Francis, M A Reddy,
D Collyer,
E Vithana,
I MacKay,
G Dawson,
A H Carey,
A Moore,
S S Bhattacharya,
R A Quinlan
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ABSTRACT: Congenital cataracts are an important cause of bilateral visual impairment in infants. In a four-generation family of English descent, we mapped dominant congenital posterior polar cataract to chromosome 11q22-q22.3. The maximum LOD score, 3.92 at recombination fraction 0, was obtained for marker D11S898, near the gene that encodes crystallin alpha-B protein (CRYAB). By sequencing the coding regions of CRYAB, we found in exon 3 a deletion mutation, 450delA, that is associated with cataract in this family. The mutation resulted in a frameshift in codon 150 and produced an aberrant protein consisting of 184 residues. This is the first report of a mutation, in this gene, resulting in isolated congenital cataract.
The American Journal of Human Genetics 12/2001; 69(5):1141-5. · 10.60 Impact Factor
