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Scientists fish out a mutation that causes Cystinosis, may help faster diagnosis

  • A model of a kidney
    A model of a kidney

Photo: Siddharth Kankaria / Research Matters

Growth impairment, vision problems and chronic kidney ailment are hallmarks of cystinosis, a rare genetic disease that affects children, who, in most cases, do not survive into their adulthood. The disease affects one in about 250000 children worldwide and many of them go undiagnosed in the initial stages, only to be detected at a later stage when complications develop in the kidneys. Now, a new study by researchers and doctors at the Indian Institute of Science and Education Research (IISER), Mohali, and the Madras Institute of Orthopaedics and Traumatology (MIOT), Chennai, may have clues to detecting this disease early on in Indian patients, thus opening up possibilities of early diagnosis and treatment.

Cystinosis is caused by the accumulation of the amino acid ‘cystine’ within cells, forming crystals that can build up and damage the cells. The accumulation is caused by abnormal transport of cystine from lysosomes, which are cell organelles responsible for destroying unwanted proteins and reducing them to their amino acid constituents. Normally, the amino acids generated from unwanted proteins, are pumped out of the lysosome through protein transporters plugged to the lysosomal membrane that act as a channel. However, in patients with cystinosis, the transporter meant for pumping cystine malfunctions, resulting in the accumulation of cystine inside the lysosomes. This hoarding of cystine can ultimately kill cells, leading to kidney failure, loss of vision, stunted growth, weight loss and hypothyroidism.

In this study, Dr. Anup Deshpande, Prof. Anand Kumar Bachhawat from IISER Mohali and Prof. Rajan Ravichandran, head of nephrology at MIOT Institute of Nephrology Chennai, studied three Indian patients between the age of 7 to 13 years and found a mutation that may be quite common in Indian patients.  The mutation is in the gene CTNS that codes for the protein transporter responsible to transfer cystine from lysosomes. A protein transporter like any other protein is made up of a chain of amino acids, the sequence of which is determined by the gene CTNS. A mutation in that gene may result in the substitution or deletion of an amino acid in the chain, thus rendering the transporter incapable of its function. The researchers found that one such mutation changed the amino acid ‘serine’ into a ‘phenyl alanine’ thus rendering the transporter faulty. “The prevalence of this mutation could eventually be important from the diagnostic perspective if this mutation is indeed the most prevalent one amongst Indian patients. However molecular analysis of more patients is important”, remarks Dr. Anup Deshpande, the first author of the study.

Nature has its way of retaining functionally important amino acids that remain unchanged even with evolution and the amino acid serine is one such. The researchers examined the CTNS gene sequence in a variety of organisms - mouse, frog, fish, yeast and the plant Arabidopsis thaliana (Thale cress) and found that the amino acid serine remained the same in all these organisms. This showed that serine is a ‘highly conserved’ amino acid sequence and a small mutation to its structure could cause havoc in protein transport. “Since this mutation is known to cause complete abolishment of the transporter activity, the disorder can be presumed to aggravate at faster pace”, explains Prof. Anand K. Bachhawat, on the effects of mutation in CTNS in patients with cystinosis.

Cystinosis, if detected early enough, can be treated with a drug Cysteamine, which provides relief for the patients and could roughly extend their life span to 35 years – a longer lifespan compared to 10 to15 years when left untreated. However, the drug is quite expensive and needs to be imported as there are no Indian pharmaceutical companies manufacturing the same. The delay in accurate diagnosis and reporting of the disease further makes matters worse.

This study is a step in the direction of making diagnosis of cystinosis easier at a molecular level in Indian patients. In cases where symptoms alone cannot ascertain the detection of the disease, this simple screening for mutation will unequivocally hit the nail on the disease. “Faster diagnosis can ensure speedy treatment and alleviate the suffering of the patient to a very great extent. This is important because cystinosis diagnosis has been relatively delayed in this country with detection often occurring when the patients arrive with severe kidney problems”, signs off Prof. Ravichandran.