viernes, 23 de enero de 2015

Glue ear – how problems with facial muscles could be a cause

Glue ear – how problems with facial muscles could be a cause

Posted on: Friday, January 23, 2015 by Tracey Pollard
Dr Jennifer Fuchs is an Action on Hearing Loss-funded student who recently obtained her PhD from Kings College London, working in Dr Abigail Tucker’s lab.
Their work was recently published in the journal Human Molecular Genetics, investigating the influence of facial muscle size on a person’s susceptibility to middle ear inflammation, and in this blog they tell us more about what they found.

The middle ear and otitis media (glue ear)

Hearing is one of our most developed senses and plays a crucial role in communication and learning. The components of the hearing apparatus are arranged serially, and carry sounds from the external ear, through the middle ear and finally into the inner ear. The ear canal and its pinna (which make up the external ear) work as a funnel, conducting sound waves towards the eardrum, a thin layer which separates the external from the middle ear. Sound waves vibrate the eardrum and are then transmitted across the middle ear to the inner ear where the sound information is processed and sent to the brain.
Any alteration in this chain of events can result in hearing loss, which can be classified as either conductive, resulting from defects of the external and middle ear structures or sensorineural, which is caused by inner ear problems.
Microscope image of otitis media in a mouse middle earConductive hearing loss is often caused by fluid build-up in the middle ear due to inflammation (called glue ear, see image). If the inflammation persists and becomes chronic, the lining of the middle ear reacts by thickening and releasing inflammatory cells into the middle ear, and it also produces more fluid (mucus) in an attempt to trap invading bacteria. Fluid and inflammatory cells surround the ossicles (tiny bones in the middle ear) and prevent their movement, so less sound information reaches the middle ear and causes hearing loss. The inflammation is often caused by environmental factors, such as bacteria or viruses; however, there is strong evidence for genetic factors which increase susceptibility to the disease.

The Eustachian tube and its function

As the air filled middle ear is enclosed between the outer and inner ear, it faces two main issues: keeping the system clean and maintaining air pressure. These essential conditions are regulated by the Eustachian tube, which connects the middle ear cavity to the back of the mouth. The Eustachian tube is normally closed to protect the middle ear from food and bacteria. However, during yawning, swallowing, or due to pressure changes, the muscles near the tube (called paratubal muscles) contract, opening and closing it to maintain pressure in the middle ear. In an adult, the Eustachian tube is vertical and this helps to drain fluid from the ear. Abnormal positioning of the tube or a constantly opened or closed Eustachian tube impairs middle ear ventilation, leading to a higher risk of inflammation.

Mouse models can help us understand the genetics behind glue ear

As genetic studies in humans only give limited information, mouse models have been introduced to examine the causes of glue ear development. One glue ear mouse model that has only been identified recently by our group is called the Df1 mouse, which has inflammation mostly in only one ear (unilateral glue ear). These mice are a model of human 22q11.2 Deletion Syndrome, a disease caused by loss of a series of genes from one particular chromosome. Loss of these genes causes cardiovascular defects and abnormal facial development, including cleft palate. In addition, patients have hearing loss and glue ear. Df1 mice lack fewer genes than people with the human condition but still have key features of the human syndrome, such as inflammation of the middle ear. They are therefore ideal models to study underlying genetic causes of the disease. One of the genes that is missing in the Df1 mouse, called T-box transcription factor 1 (Tbx1), has been identified as the key gene responsible for the disease; mice which only lack Tbx1 also develop glue ear.

Our research

Using both the Df1 and Tbx1 mouse models to understand the high risk of glue ear in human patients with 22q11.2 Deletion Syndrome, we focussed on the Eustachian tube, as it is a structure crucial for middle ear ventilation.
Tests to evaluate how well the Eustachian tube works in these mice revealed that the mutant mice had impaired ability to clear the middle ear. A dye was injected into both middle ears of non-mutant mice, and it took 5 minutes to be drained from both ears via the Eustachian tube into the mouth. The dye used was strongly fluorescent, enabling it to be traced through the roof of the mouth. In mutant mice, however, clearance of the dye was delayed and some mice only cleared dye from one ear but not the other. Problems in middle ear clearance are linked with build-up of fluid in the middle ear leading to the onset of inflammation (glue ear).
The candidate gene for glue ear in our mutants, Tbx1, has a role in muscle development. As the paratubal muscles, especially one called the levator veli palatini muscle, are crucial for Eustachian tube function, we measured their size in mutant compared to non-mutant mice. Our results show that the levator veli palatini muscle is smaller in mutant mice. In addition, activity of a gene that has an early role in muscle development was reduced, indicating that the smaller muscle size is due to early events in the developing embryo. Interestingly, the influence of this mutation on muscle size in the mutant mice was variable and could even be different in the same mouse. In young mutant mice with early signs of unilateral glue ear, the inflamed side had smaller muscles than the uninflamed ear. The smaller the muscle, the higher the risk of middle ear inflammation. In conclusion, our glue ear mice are the first mouse models that link a smaller paratubal muscle size to an increased risk of developing middle ear inflammation. Hopefully, our research will help to pioneer new treatments and preventive methods for glue ear. One possibility could be targeted training of someone’s paratubal muscles. Specific exercises might be able to strengthen genetically smaller muscles and thus prevent the development of glue ear.

This research was published last month in Human Molecular Genetics

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