In a major breakthrough, the team led by Dr Jai Rup Singh, Coordinator, Centre for Genetic Disorders, Guru Nanak Dev University in association with Dr Daljit Singh, a renowned ophthalmologist, supported by scientists from the National Institute of Health, USA, Institute of Human Genetics, Berlin, Germany, has identified three new cataract-causing genes in Indian families after 15 years of research .
The three genes identified by the scientists are ‘Fan Shaped Cataract’, ‘Cerulean Cataract’ and ‘Sutural Cataract’. These would ultimately help in prevention and cure for not only congenital cataract but also senile cataract.
Dr Jai Rup Singh said that this research had been carried out on congenital cataract for the past 30 years. He said the Centre for Genetic Disorders of the University had collected DNA samples from more than 2400 cases suffering from genetic diseases of the eye and had maintained one of the largest DNA database in the world for congenital cataract. He said the DNA analysis on these cases was initiated in 1990 when the Centre was established. At present the DNA analysis on more than 700 families of congenital cataract is still in progress.
Dr Singh said congenital cataract affects about 3 per 10000 newborns and is one of the significant causes of blindness in children and also life-long visual disability. He said present discoveries are the result of long painstaking efforts undertaken by the scientists at the Centre for Genetic Disorders in which the individual members of these families had been pursued for periods ranging from 3-5 years. He said the discoveries have been reported almost simultaneously in the recent issues of the reputed international journals. The first breakthrough was reached in 2001 when two new genes were identified. Now three new genes have been localized in the Indian families.
Prof Jai Rup Singh disclosed that the identification of the defect at the DNA level would ultimately facilitate in the identification of the exact causative agent for congenital cataract.
He said the novel type of cataract has been named as “Fan-shaped” cataract. The responsible gene is localized on the long arm of 21st chromosome and a single base pair change in it causes the congenital cataract that is exclusively associated with microcornea.
This family first came to notice when an affected child was seen at Dr Daljit Singh Eye Hospital. The subsequent follow-up of this family revealed the presence of similar defect in individuals spreading over four generations. The blood samples from 19 individuals from this family were analysed at DNA level with more than 400 microsatellite markers to trace the exact location of the disease causing gene. After narrowing down the region on the 21st chromosome, further sophisticated molecular analyses were undertaken to trace the exact defect in the gene itself and its consequences on the eye.
The coordinator said defect in this gene, i.e., the causative mutation has also been traced. It is being caused by a single nucleotide alteration in which a base Cytosine (C) of the 116th codon has been replaced by another base Thymine (T). This small sub-molecular replacement results in the replacement of an amino acid called Arginine by Cysteine which consequently modifies the structure of the alpha-crystallin that is synthesized by this gene and which is an essential lens protein. This alteration ultimately leads to the causation of this typical “fan-shaped” type of cataract and microcornea.
Dr Jai Rup Singh said the other two discoveries, also pertain to, hitherto not reported, two new loci for two types of congenital cataract. The second report is about the mapping for the first time a gene for congenital cataract, known as, “cerulean cataract” on 16th chromosome. The detailed molecular studies in the family led to the identification of a new type of mutation that had also not been identified earlier in the responsible gene, localized on this chromosome. This mutation was found in a large family of three generations in which 12 individuals were affected and the analysis took almost four years to complete, he added.
Talking about another research in this field, Dr Jai Rup Singh said the third report is regarding the discovery of the first ever localization of the gene for “sutural cataract” on chromosome number 19. It is also the first report of identification of hereditary hyperferritinemia-cataract syndrome in a family of Indian origin. He said this breakthrough reported in the February 2006 issue of international journal “Molecular Vision”, was achieved through the sophisticated molecular analysis undertaken on 27 individuals belonging to a 4 generation family and also took over 3 years to complete.
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