Penn study sheds light on genetics of most prevalent sensory deficit in humans.

One in 500 newborns fail their newborn hearing screens and are diagnosed with hearing loss, making this the most prevalent sensory deficit in humans. About half of these cases of early hearing loss in developed countries have an identifiable genetic cause, with mutations in over 100 different genes identified so far.

Mutations in the majority of these genes result in isolated hearing loss (meaning not part of a more complex hearing loss syndrome such as Usher Syndrome). These cases are called non-syndromic sensorineural hearing loss, or SNHL, where an abnormal inner ear function is the only diagnostic feature. Despite the large number of identified hearing loss genes, the cause of inherited hearing loss remains a mystery in more than half the children.

A trio of researchers from the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) found mutations in a master-switch protein called Epithelial Splicing-Regulatory Protein 1 (ESRP1) in individuals with SNHL.

This research was published in the journal Developmental Cell.

In general, what connects most of the unexplained hearing-loss cases is that protein building in the cochlea during development goes awry. The cochlea has the all-important job of transforming mechanical energy in the form of sound waves into electrical signals that run along auditory nerves to the brain.



Overall, ESRP1 determines how RNAs expressed in epithelial tissues are spliced together. This is achieved by splicing different exons (the sequence of DNA that codes for proteins) together in alternative ways to produce more than one messenger RNA (mRNA) from the same gene. These mRNAs go on to make different versions of encoded proteins. Co-senior authors Doug Epstein, PhD, a professor of Genetics, and Russ Carstens, MD, an associate professor of Renal-Electrolyte and Hypertension, worked with Ian Krantz, MD, a professor of Pediatrics, and a family he cares for at the pediatric hearing clinic he directs at CHOP.

In the family, two out of the six children use cochlear implants for their hearing loss. The team sequenced the entire exome in the siblings and parents and found damaging mutations in ESRP1, with associated hearing loss. Using induced pluripotent stem cells made from affected and unaffected family members they showed that RNA splicing switches were restored when the ESRP1 mutation was corrected with CRISPR-CAS9 gene editing. “We were excited to see these results as they provided clear evidence that ESRP1 mutations were responsible for the splicing defects in the affected children,” Epstein said. The gene editing experiments were performed by Penn co-authors Kiran Musunuru, MD, PhD, and postdoctoral fellow Chris McDermott-Roe.

Krantz and CHOP research intern, Ricky Tilton, MD, identified the ESRP1 gene mutations central to this family’s case. “Beyond providing a long sought after answer for this family, this research is exciting as it implicates this critical molecular pathway with a developmental diagnosis in humans for the first time and helps shed light on a novel contributor to hearing loss that may lead to new approaches for therapeutics down the road,” said Krantz, who is also director of Roberts Individualized Medical Genetics Center in the Roberts Collaborative for Genetics and Individualized Medicine at CHOP.

“The act of hearing is based on hair cells in the ear that are like piano keys sensitive to vibrations at different pitches,” Epstein said. According to John Germiller, MD, PhD, director of Clinical Research in the Division of Otolaryngology at CHOP, the two siblings in the family had a defect in the vestibular canals of their ears, but no obvious defect in the cochlea. In addition, loss of the Esrp1 gene in mice leads to changes in the shape of the inner ear that i