genetics

Family Ties

By Ava Finnerty

Ava’s mother, Sonia, had a hearing loss but never disclosed it to anyone.

Ava’s mother, Sonia, had a hearing loss but never disclosed it to anyone.

My mother Sonia, born and raised in Wales, was the first person I knew with a hearing loss. She concealed it for many years. In my adolescence and young adulthood, I came to learn of her hearing loss, my grandmother’s, and, eventually, my own.

During World War II, my mother served in the Women’s Air Corps in Britain, where it was her duty to (wo)man the barrage balloons on the White Cliffs of Dover. It was there she met and married my father, John Jessen, a U.S. Army Sergeant preparing for D-Day. During the war she gave birth to my oldest brother, and then they both emigrated to the U.S. in 1946 to reunite with my father.

My parents moved to a veterans housing project in Bayonne, New Jersey, to raise our family. My mother was a very private person who largely refrained from sharing her medical issues with my two brothers, my sister, and me. I have a vague memory of her having some kind of ear surgery in the early 1950s, when I was 5 or 6 years old, but I did not receive an explanation. 

Every time we went swimming, my mother plugged her left ear with a large wad of cotton and covered her head with a bathing cap. She told us she had a “hole” in her ear that needed to be protected from water. Incidentally, my mother helped tend bar at my father’s parents’ bar, The Viking, before becoming pregnant with me, but I later learned for certain her hearing loss was not caused by noise.

A Family Inheritance

A strict parent, my mother believed “children should be seen and not heard,” so I thought she often remained silent in response to my questions on purpose, and not because she literally could not hear me. It was only when I was a teenager that my mother told me the truth about her hearing. She had a severe hearing loss, but she did not treat it. Her small group of friends likely provided some support for her untreated condition.

My mother inherited her hearing loss from her mother, Bessie, who was profoundly deaf. Grannie still lived in the small Welsh village of Pontypool, where I visited her occasionally, first when I was 20, before my own hearing loss had been identified.

Shown with extended family, Ava (second from right) traces her roots to Wales through her mother Sonia.

Shown with extended family, Ava (second from right) traces her roots to Wales through her mother Sonia.

Grannie was a voracious writer—I suppose by necessity, because she did not wear hearing aids. She was keenly in touch with her surroundings, able to sense vibrations and read lips adeptly. Relying heavily on her vision, she was more cognizant of others’ facial expressions and body language than most with typical hearing. 

At my wedding Grannie impressed me with her grace as a dancer, using the feelings of the bass and drums to move rhythmically. She was a strong and confident woman who’d grown resilient living as a mother and grandmother with a hearing loss during World War II. 

A Gradual Process

My own difficulty hearing came on so gradually it was hard to notice. But I do remember vividly the day I realized the difference between my left and right ears. I was then a parent of three young children, living in Bayonne in a two-family house with my mother. I was cooking while cradling the phone between my right shoulder and right ear. 

At one point in the conversation I switched the phone to my left ear and realized I could not hear what was being said. Despite this realization, I compensated for some time, relying on my “good” ear for conversation. It is truly amazing what a person can get accustomed to not having!

Around this time I could tell that my hearing loss was affecting my work. I was well into my career as a high school English teacher. At first, I attributed my inability to understand my students to their mumbling or mouth-covering. But, as the problem worsened, I knew it was me, not them. Only later did I learn my colleagues thought I was aloof because I would not acknowledge their greetings!

I developed a meaningful relationship with my mother, incidentally, during the onset of my own hearing loss. She and I cared for my father, helping him with home kidney dialysis every other day, and formed a very close bond. After his death, we spent many hours talking together, and I told her about the difficulty I had hearing my students.

Even though I knew of my mother and my grandmother’s hearing loss, I had concluded I had a buildup of earwax in my left ear. My husband Joseph, who was the chief echocardiography technologist for New York Hospital, was able to refer me to an audiologist at New York Weill Cornell Hospital. 

There I learned I had almost no earwax buildup—but I did have a significant hearing loss. I was diagnosed with a 78 percent loss in my left ear and a loss of close to 30 percent in my right. 

Successful Surgery

My left ear’s hearing loss was due to otosclerosis, an abnormal growth of bone in the middle ear. Otosclerosis is commonly thought to be inherited but its causes remain unclear. Scientists cite measles infections, stress fractures to tissue surrounding the inner ear, and immune disorders as possible causes. My doctor noted my otosclerosis was accelerated by my pregnancies, and research has since suggested this is possible.

I had a successful stapedectomy on my left ear, a surgical procedure that replaces the stapes bone with a prosthetic device so the bones in the middle ear can again vibrate in response to
sound and hearing is restored. The procedure was minimally uncomfortable but did cause severe vertigo, which I was able to control with medication. 

In the late 1980s, my mother finally chose to pursue hearing aids but wore them rarely because they emitted a very high-pitched sound. Later in her life, she stopped wearing them completely. Since we shared the two-family home, my family and I always knew what Grandma was playing on her television or radio upstairs at maximum volume. And we lost count of the number of times she shouted “whadjasay?!” to my father.

Mom became increasingly withdrawn. She never wanted to go out on dinner dates or socialize with friends. Only in recent years, after her passing, have I come to understand this preference for isolation.

Over the decades that followed, the hearing in my right ear slowly diminished and I found it increasingly difficult to manage at social events. I wanted to undergo a second stapedectomy, but the audiologist told me this wasn’t recommended. 

I was fitted for hearing aids instead. The audiogram showed a moderate hearing loss in my left ear and a severe loss in my right with difficulty hearing low frequencies in both. No wonder I could not hear the deep-voiced young men speaking in class!

The audiologist asked if I wanted access to sounds at 180 or 360 degrees. I said 360 because I wanted to hear what my students were saying behind my back. I always told my students that although I wore hearing aids, they needed to speak clearly and be aware that I sometimes surprised myself by what I was able to hear. I specifically told my students to never say “never mind” if I asked them to repeat themselves or speak up, but to repeat and rephrase what they said.

Vigilant About Hearing Well

Ava (middle) and her two daughters.

Ava (middle) and her two daughters.

This was in 2011, when I was 62 years old, and I’ve vigilantly worn my hearing aids since. The devices have, for certain, added to my quality of life. They are not perfect, but I consider them an absolute necessity if I want to hear my grandchildren and other family members. I am a music lover, play-goer, and movie fan. And had I not begun wearing them, I surely would have retired from my teaching career earlier than I wanted to. 

I supplement my hearing aids with simple requests and tools. I have no problem telling someone, “I don’t hear as well as I would like to. Could you say that again?” I retired in 2014, after 42 years of teaching high school English, and then was elected to be a Bayonne Board of Education trustee in 2015. During our meetings I prefer to sit at or near the head of the table to read the lips of the person speaking. 

I use closed captions at home watching television. When I babysit, I often go to my grandchildren’s bedroom doors to check on them because I am not sure if they are crying. I love baby monitors that not only light up but also have video for me to easily check. 

Both my daughter and daughter-in-law are aware of the genetic predisposition for otosclerosis. In fact, my daughter thinks that her 16-year-old daughter may have some hearing loss. My advice to her was to pay attention—but also that there is a great distinction between “hearing” and “listening,” especially when it comes to adolescents! 

Ava Finnerty lives with her husband Joseph in New Jersey. A retired English teacher, she serves on the Bayonne Board of Education as a trustee. Their adult children are Kristen, also an English teacher; Jill,
a music teacher; and Sean, a U.S. Navy veteran who served in Iraq. This article originally appeared in the Summer 2019 issue of Hearing Health magazine. For references, see
hhf.org/summer2019-references.

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New Insights into the Development of the Hair Cell Bundle

By Yishane Lee

Recent genetic studies have identified that the protein Ripor2 (formerly known as Fam65b) is an important molecule for hearing. It localizes to the stereocilia of auditory hair cells and causes deafness when mutations disrupt its function.

In a study published in the Journal of Molecular Medicine in November 2018, Oscar Diaz-Horta, Ph.D., a 2017 Emerging Research Grants (ERG) scientist, and colleagues further show the role the protein plays by demonstrating how it interacts with other proteins during the development of the hair cell bundle. The team found that the absence of Ripor2 changes the orientation of the hair cell bundle, which in turn affects hearing ability.

Ripor2 interacts with Myh9, a protein encoded by a known deafness gene, and Myh9 is expressed in the hair cell bundle stereocilia as well as its kinocilia (apices). The team found that the absence of Ripor2 means that Myh9 is low in abundance. In the study, Ripor2-deficient mice developed hair cell bundles with atypically localized kinocilia and reduced abundance of a phosphorylated form of Myh9. (Phosphorylation is a cellular process critical for protein function.)

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Another specific kinociliary protein, acetylated alpha tubulin, helps stabilize cell structures. The researchers found it is also reduced in the absence of Ripor2.

The study concludes that Ripor2 deficiency affects the abundance and/or role of proteins in stereocilia and kinocilia, which negatively affects the structure and function of the auditory hair cell bundle. These newly detailed molecular aspects of hearing will help to better understand how, when these molecular actions are disrupted, hearing loss occurs.

A 2017 ERG scientist funded by the Children’s Hearing Institute (CHI), Oscar Diaz-Horta, Ph.D., was an assistant scientist in the department of human genetics at the University of Miami. He passed away suddenly in August 2018, while this paper was in production. HHF and CHI both send our deepest condolences to Diaz-Horta’s family and colleagues.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.

 
 
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Headlines in Hearing Restoration

By Yishane Lee

The cornerstone of Hearing Health Foundation for six decades has been funding early-career hearing and balance researchers through its Emerging Research Grants (ERG) program. Many ERG scientists have gone on to obtain prestigious National Institutes of Health (NIH) funding to continue their HHF-funded research; since 1958, each dollar awarded to ERG scientists by HHF has been matched by NIH investments of more than $90. Within the scientific community, ERG is a competitive grant awarded to the most promising investigators, and we’re always especially pleased when our ERG alumni who are now also members of or affiliated with our Hearing Restoration Project consortium make headlines in the mainstream news for their scientific breakthroughs.

Hair cells in the mouse cochlea courtesy of the lab of Hearing Restoration Project (HRP) member Andy Groves, Ph.D., Baylor College of Medicine.

Hair cells in the mouse cochlea courtesy of the lab of Hearing Restoration Project (HRP) member Andy Groves, Ph.D., Baylor College of Medicine.

Ronna Hertzano, M.D., Ph.D. (2009–10): Hearing Restoration Project consortium member Hertzano, an associate professor at the University of Maryland School of Medicine, and colleagues identified a gene, Ikzf2, that acts as a key regulator for outer hair cells whose loss is a major cause of age-related hearing loss. The Ikzf2 gene encodes helios, a transcription factor (a protein that controls the expression of other genes). The mutation of the gene in mice impairs the activity of helios in the mice, leading to an outer hair cell deficit.

Reporting in the Nov. 21, 2018, issue of Nature, the team tested whether the opposite effect could be created—if an abundance of helios could boost the population of outer hair cells. They introduced a virus engineered to overexpress helios into the inner ear hair cells of newborn mice, and found that some mature inner hair cells became more like outer hair cells by exhibiting electromotility, a property limited to outer hair cells. The finding that helios can drive inner hair cells to adopt critical outer hair cell characteristics holds promise for future treatments of age-related hearing loss.

Patricia White, Ph.D. (2009, 2011), with Hearing Restoration Project member Albert Edge, Ph.D.: White, a research associate professor at the University of Rochester Medical Center, Edge, a professor of otolaryngology at Massachusetts Eye and Ear and Harvard Medical School, and team have been able to regrow the sensory hair cells found in the mouse cochlea. The study, published in the European Journal of Neuroscience on Sep. 30, 2018, builds on White’s prior research that identified a family of receptors called epidermal growth factor (EGF) that is responsible for activating supporting cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. In mice, EGF receptors are expressed but do not drive regeneration of hair cells, so it could be that as mammals evolved, the signaling pathway was altered.

The new study aimed to unblock the regeneration of hair cells and also integrate them with nerve cells, so they are functional, by switching the EGF signaling pathway to act as it does in birds. The team focused on a specific receptor called ERBB2, found in supporting cells. They used a number of methods to activate the EGF signaling pathway: a virus targeting ERBB2 receptors; mice genetically altered to overexpress activated ERBB2; and two drugs developed to stimulate stem cell activity in the eye and pancreas that are already known to activate ERBB2 signaling. The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events: Supporting cells began to proliferate and started the process of activating other neighboring stem cells to lead to “apparent supernumerary hair cell formation,” and these hair cells’ integration with the network of neurons was also supported.

This was prepared using press materials from the University of Maryland and the University of Rochester. For more, see hhf.org/hrp.

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Prenatal Intervention May Be Necessary for Usher Syndrome Treatment

By Carol Stoll

Usher syndrome is a hereditary disorder that affects 1 in 20,000 people worldwide and causes concurrent hearing and vision loss. Though currently there is no cure, scientists have begun to understand the molecular mechanisms of hearing loss in Usher syndrome by identifying the specific mutations in genes associated with auditory hair cell malfunction. Gene-specific targeting has been used to target Usher mutations and restore hearing, but the effectiveness and best timing of the treatment is still being investigated in mouse models. Recent research published in JARO by Emerging Research Grants (ERG) recipient Michelle Hastings, Ph.D., and colleagues shows that early administration of a genetic targeting treatment is critically important for repairing outer hair cells and thus rescuing hearing in those with genetic disorders like Usher syndrome.

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Hastings’ research focuses on type 1 Usher, which is the most severe of three subtypes and is associated with six genes. One of these genes, USH1C, contains the instructions to create a protein that localizes to auditory hair cells and helps to maintain their bundle structure and ability to detect sound waves. A mutation in USH1C causes this protein to be cut short and malfunction, and is thus responsible for type 1C Usher in humans. Adding, or “knocking-in,” the mutation to mouse DNA causes symptoms similar to those of human patients with type 1C Usher. These Usher mice exhibit hearing and vision loss as well as deficits in balance, little or no auditory-evoked brainstem response (ABR), and abnormal eye tests called electroretinograms. The hearing loss is linked to defective or missing inner and outer hair cells in the cochlea of the inner ear.

Antisense oligonucleotide (ASO) therapy is a gene-specific targeting therapy previously used by Hastings and her colleagues to rescue hearing in Usher knock-in mice. ASOs are small strands of nucleotides (the building blocks of DNA and RNA) that are specifically synthesized to bind to the disease-causing mutation site of RNA and block it from creating defective RNA and proteins. The ASO therapy targeting the USH1C mutation was administered to the Usher mice a few days after birth. Hearing was rescued and ABR improved, which is indicative of improved inner hair cell function. However, function of the outer hair cells, which surround the inner hair cells and are responsible for amplifying sounds, was not tested.

Hastings’ most recent study, with Jennifer Lentz, Ph.D.’s research group, investigated whether the timing of ASO treatment is important for rescuing outer hair cells in addition to inner hair cells for full hearing rescue. ASO therapy was administered to knock-in Usher mice of varying ages, and then outer hair cell function was tested by measuring distortion product otoacoustic emissions (DPOAEs) in 1-, 3-, and 6-month-old mice. When two tones are presented in the ear canal, outer hair cells that function normally respond by producing amplified sounds known as DPOAEs. In Usher mice, DPOAEs are not detected, which indicates loss of outer hair cell function. ASO treatment was able to recover outer hair cell function measured by DPOAEs when it was administered one day after birth. However, the treatment was not effective if first administered on or after postnatal day five.

The results of this study indicate that there is a developmental window of time when USH1 gene expression is needed to properly develop auditory hair cells, and thus early genetic treatment is essential for hearing rescue of those with Usher syndrome. In humans, hair cell development occurs early in pregnancy, and thus ASO treatment would likely require very early prenatal intervention. ASOs have been approved for clinical use for a number of different diseases in humans, but more animal research is necessary before moving to clinical trials for ASO therapy for Usher syndrome. Hastings has also published research on testing ASO therapy on prenatal mice, and found that injecting ASOs in the amniotic cavity of pregnant mice can in fact access the cochlea. Hastings’ research has improved the scientific community’s understanding of the functions of inner and outer hair cells and brings us closer to developing a cure for Usher syndrome.

Michelle Hastings, Ph.D., was a 2009 and 2011 Emerging Research Grants scientist. For more, see “Rescue of Outer Hair Cells With Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment” in The Journal of the Association for Research in Otolaryngology.

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