AMRITSAR:  The Centre for Genetic Disorders of GNDU (Guru Nanak Dev University) has identified ‘three new cataract causing genes in Indian families’. This research was the result of 30 years research labour in the field of OPHTHALMOLOGY. The three Genes identified by the scientists are 'Fan Shaped Cataract', 'Cerulean Cataract' and 'Sutural Cataract'.

The research team led by Prof. Dr. Jai Rup Singh, Coordinator of Centre for Genetic Disorders of the GNDU in association with Dr. Daljit Singh, an Ophthalmologist of international repute, along with scientists from the National Institute of Health, USA and from the Institute of Human Genetics, Berlin (Germany), has achieved a major breakthrough by identifying and localizing these three new cataract-causing genes in Indian families.

Dr. Jai Rup Singh sharing his research work to the media said that this research has 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 the 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 these discoveries have been reported almost simultaneously in the recent issues of the reputed international journals. The latest report appeared in the 22nd May 2006 issue of the prestigious journal of USA, “Molecular Vision”. He said the first breakthrough came 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. These would ultimately help in prevention and cure for not only congenital cataract but also senile 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.

He said this family first came into notice when an affected child was seen at Dr. Daljit Singh Eye Hospital in Amritsar. The subsequent follow-up of this family by the Centre for Genetic Disorders, revealed the presence of similar defect in individuals spreading over four generations. The blood samples from nineteen 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. He said 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, he added.

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). He said 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. Dr. Jai Rup said 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. He said 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 4 years to complete, he added. He said that in the affected individuals’ DNA, the nucleotide base Adenine (A) is substituted by the base Guanine (G) at position 890 of a gene known as MAF. This leads to change of an amino acid Lysine with Arginine at the 297th position, that ultimately leads to this particular type of cataract.
     
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.
     
Dr. Singh said the molecular analysis in this family also involved screening of all the members of the family with over 400 microsatellite markers that led to the localization of the gene on 19th chromosome. Further analysis revealed the exact defect being due to a mutation in the gene known as FTL in which a base Guanine (G) had been replaced by Adenine (A) at position 32 that caused high levels of L-ferritin protein which precipitated in the lens and caused cataract.
     
With the identification of the exact genetic causes at the molecular level for these new types of congenital cataract. He said it is now technically feasible to prenatally ascertain whether the child to be born would suffer from any of these particular congenital cataracts or not. In addition, this discovery paves the way for ascertaining the complex phenomenon of genotype - phenotype correlation that exists with respect to congenital cataract as well as other genetic disorders he added.
     
Dr. Jai Rup Singh said with the reporting of these three genes, the total number of new genes for congenital cataract that have been localized by the team have come to five which is a unique achievement in itself, because till now, world-wide, only about 30 genes have been localized for congenital cataract. The two genes that were earlier localized in 2001 have already been assigned unique international OMIM identification numbers and these three genes are also expected to be assigned such OMIM numbers shortly.