A group of researchers led by Dr. Albert Edge at Mass Eye and Ear have identified the reason deafness occurs in a rare syndrome known as Norrie disease. Researchers discovered that the Norrie Disease Protein (NDP) is lacking in patients with the disease and is essential for maintenance and survival of hair cells in the cochlea – the cells responsible for hearing. Their findings were published in PNAS.
Norrie disease is an inherited disorder caused by more than 100 different mutations in the NDP gene located on the X chromosome, which leads to insufficient development of the blood vessels in the retina and the inner ear before birth when infants are still developing. Infants who are born with Norrie disease are born blind and lose their hearing later around the age of 12.
How is Norrie Disease Protein inherited?
The NDP gene is located on the X chromosome, and the X chromosome determines our gender together with the Y chromosome. Females have two X chromosomes whereas males have one X and one Y chromosome. Only one functioning copy of the NDP gene is required for normal blood vessel development of the retina and the inner ear; thus, only males can inherit Norrie disease. Below are possible genotypes that can occur:
If the mother is a “carrier” and the father is healthy:
- Each son has a 50% chance of being affected
- Each daughter has a 50% change of being a carrier
If the father is affected and the mother is healthy:
- None of his sons will be affected
- All of his daughters will be carriers
The research study
Researchers had originally thought that vascular issues caused Norrie disease and led to vision and hearing loss; however, their findings proved that a lack of the NDP gene is the real cause of hearing loss. They were able to conclude this by analyzing knockout mice that lacked the gene and found that the mice had abnormalities in their cochlear hair cells.
By further analyzing gene expression of NDP, the researchers found that NDP controls a network of transcriptional regulators that are required for maturation and maintenance of cochlear hair cells. The knockout mice that had abnormalities in their cochlear hair cells died between birth and two months of age, which corresponded with the time course of progressive deafness. This shows that hair cells appear to be normal at birth, but as they mature, some of them die and others have issues with expression of proteins.
Methods that lead to potential treatments
There are two methods that lead to potential treatments of Norrie disease. One of the methods is stimulating the Wnt signaling pathway, which had previously been found to be important for hair cell regeneration. Researchers were able to overexpress a molecule called B-catenin in the newborn genetic knockout mouse, which replicated the effects of NDP on hair cells and resulted in normal hearing. This demonstrates that the Wnt signaling pathway may be a target for possible treatment.
The second modality is overexpressing NDP in cells adjacent to the hair cells so that these supporting cells would secrete NDP into the area surrounding the hair cells. Once those cells secrete NDP, the protein bound to the hair cells and rescued deafness in the mice.
“There are a number of implications of this work, one that clearly NDP is a part of the overall picture of Wnt signaling in the normal ear,” said Dr. Edge. “While that work is very early and experimental, this new study strengthens our hypothesis that Wnt signaling is important for regenerating hair cells.”
Researchers believe that if a therapy for hearing loss in Norrie disease were available, it should be possible to initiate treatment before its onset.
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