By Chetana Sachidanandan & team
(CSIR-Institute of Genomics and Integrative Biology, New Delhi)
CHARGE syndrome is a rare birth defect that affects approximately 1 in 20,000 people around the world. That would mean that there are about 50,000 patients in India as well. CHARGE syndrome causes multiple life-threatening problems in a newborn, such as facial bone and nerve defects that cause breathing and swallowing difficulties, deafness and blindness, heart defects, genital problems and growth retardation. The children may survive and go on to live with these deficiencies if the heart and bone defects are corrected with multiple surgeries, but those without access to such support usually do not survive past their first year.
CHARGE syndrome is a result of defective embryonic development. Two-thirds of the patients with CHARGE syndrome have a sporadic mutation in the gene called CHD7.
The CHARGE syndrome is being studied by many scientific groups using different models. We at the CSIR-Institute of Genomics and Integrative Biology, Delhi, have been studying it in the embryo of a small fish called zebrafish that is found in the waters of eastern India. These fish are ideal for this kind of study because their tiny embryos are transparent, making it possible to see inside the animal and watch in real time how the organs develop.
We have recreated CHARGE syndrome in the zebrafish by modifying the fish CHD7 gene, and we find that these embryos have problems very similar to the human babies diagnosed with the condition. We discovered that they had defects in the nerves that control the digestive tract and neuronal conduction as well. These defects have not previously been noticed by doctors in infants with CHARGE syndrome, most likely because such deep-lying defects are not apparent on gross examination of patients. But there have been odd reports of CHARGE patients complaining of chronic constipation, which could be an indication that such defects exist in humans as well. Our findings mean that the doctors can now look specifically for these defects as well and provide better support to the patients.
While studying the CHARGE syndrome in zebrafish we discovered that CHD7 causes the condition by modifying a second gene called SOX10. The levels of SOX10 were higher than normal in the CHARGE-affected zebrafish. We wondered whether we could correct the defects in CHARGE syndrome by reducing the levels of SOX10. Doing so in the CHARGE-syndrome affected zebrafish reduced the defects in their facial bones and neurons.
This was a very important lead. It implies that if we could modify SOX10 or similar genes in a CHARGE patient, we may be able to help a baby breathe and swallow better, thus reducing their suffering and improving their chances of survival.
Thus the approach, using tiny fish, has helped open up the way to developing therapies or treatments for important birth defects such as CHARGE syndrome.