Genetics Experts Reveal Early Events in Childhood Hearing Loss

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A Children’s Hospital of Philadelphia (CHOP) expert in childhood hearing loss co-led a study detailing how a mutated gene disrupts normal development in the inner ear early in life. Although the research does not immediately suggest medical interventions for affected children, it may offer clues toward designing future treatments for children with this type of hearing loss.

Ian D. Krantz, MD, Director of the Roberts Individualized Medical Genetics Center (RIMGC) at CHOP, was a co-senior author of the paper on mutations in the ESRP1 gene, published Oct. 27 in Developmental Cell. The study team described how the mutations disrupt proteins in the cochlea, the part of the inner ear which converts sound waves into electrical signals that travel to the brain.

Genetic causes of human hearing loss are complex, with mutations in over 100 genes already known to play a role. A CHOP lab’s discovery of one such genetic contributor set the stage for the current research project. Krantz, who directs CHOP’s Genetics of Hearing Loss Clinic, had previously performed whole-exome sequencing on a patient family in whom two siblings use cochlear implants for their hearing loss. Krantz and research intern Ricky Tilton, MD, identified the ESRP1 mutations as a culprit in the siblings’ condition, but the biological pathways acted on by those mutations were largely unknown.

In the new study, Krantz, along with co-senior authors Doug Epstein, PhD, a professor of Genetics, and Russ Carstens, MD, an associate professor of Renal-Electrolyte and Hypertension, both at the Perelman School of Medicine at the University of Pennsylvania, analyzed the patients’ cells and performed studies in mutant mice.

The scientists showed that the gene mutations affected a master-switch protein, ESRP1, that regulates how portions of DNA sequences are spliced together to produce messenger RNAs. Those RNAs make other proteins, and abnormal splicing patterns give rise to defective proteins that damage the cochlea’s signal-transmitting function. What results is hearing loss. This is the first time that this important developmental pathway has been implicated in a human developmental condition.

Krantz was able to tell the family the specific cause of the hearing loss in their two children. He added that, “Our hope is that down the road, our understanding of this critical molecular pathway will lead to novel treatments for children with hearing loss.”

The RIMGC at CHOP participates in the Hospital’s Roberts Collaborative for Genetics and Individualized Medicine. John Germiller, MD, PhD, Director of Clinical Research in CHOP’s Division of Otolaryngology, also is a co-author of this study.

For more details about this study, see this Penn Medicine news release.

Contact: The Children’s Hospital of Philadelphia,