Charge syndrome is a rare genetic disorder (1 out of 10 000 births) caused by a mutation in a copy of CHD7 gene, resulting in many defects. This syndrome is recognised as being the major cause of congenital deafness and blindness. In infected children, neurological disorders increase with age. Dr Parras’ team at the Institut du Cerveau – ICM has shown that this anomaly could be related to a deficient myelination process. Their discoveries indicate that CHD7 gene is essential for oligodendrocyte maturation and myelin formation. This new potential therapeutic target could lead to the development of new treatments for people suffering from diseases due to myelination defects.
CHARGE syndrome is manifested by many congenital malformations: malformations of the eye, heart, nose, growth and psychomotor development delay, genito-urinary problems, ear deficiencies. Most patients with CHARGE syndrome show alterations of the central nervous system, with white matter defects and the formation of the myelin sheath, substance surrounding and protecting the axons allowing the rapid transmission of information in the Nervous System. This demyelination, which occurs in the brain, but also in the spinal cord, is partly responsible, in function of its location, for motor, sensory, balance and visual disorders…
Myelin sheaths are produced by brain cells called oligodendrocytes. Formed from immature precursors that are found everywhere in the brain, these cells have to switch from an immature state to a mature state. This process requires the activation of genes involved in the synthesis of myelin. For this activation, chromatin needs to be uncompressed so that the DNA of these genes is accessible : it is called chromatin remodelling. CHD7 protein being a factor in chromatin remodelling, it has proved to play a major role in oligodendrocyte maturation.
Dr Parras’ team has studied in a mouse model, the role of CHD7 in oligodendrocyte differentiation and myelin formation. They have shown that CHD7 is absent, oligodendrocytes remain blocked in an immature stage, which leads to the observed myelination defects. CHD7 is therefore necessary for oligodendrocyte maturation and is critical for myelin formation and repair. The mechanisms activated by CHD7 could be therapeutic targets to allow myelin regeneration in patients with CHARGE Syndrome, but also for patients with a loss of myelin, as in the case of multiple Sclerosis.