Two missense mutations in a specific receptor that crosses the cellular membrane (sphingosine-1-phosphate receptor 2 or S1PR2) are associated with hearing loss in two Pakistani families, said an international group of researchers led by those at Baylor College of Medicine.

“It is the first time that a mutation in the S1PR gene family has been associated with human disease,” said Dr. Suzanne Leal, director of the Center for Statistical Genetics at Baylor and a professor of molecular and human genetics at the College.

A knockout mouse model also had hearing impairment. In one of the families, a foot abnormality was associated with the hearing problem, but Leal and first author Dr. Regie Lyn P. Santos-Cortez said that the foot abnormality is most likely caused by a gene near S1PR2 and not the gene itself. Skeletal abnormalities are neither observed in mice or the other family making this unlikely to be a true syndrome.

A report on the study appears online in the American Journal of Human Genetics

A missense mutation is a change in a single nucleotide in a gene that results in the cell making a different amino acid, thus changing the protein and effect of the gene itself. 

“S1PR2 is a basic protein that affects how important genes are expressed in the inner ear. When the level of this protein is ‘knocked down,’ or deleted, in zebrafish or mice, then the defect that leads to hearing impairment appears,” said Santos-Cortez, assistant professor of molecular and human genetics at Baylor. She was trained as an ear, nose and throat specialist.

Previous studies by other groups of researchers showed that mice lacking S1PR2 had profound deafness. The defect stems from degeneration and maldevelopment, the researchers said. Analysis of the cells in the inner ears of mice that lack S1PR2 showed changes in a portion of the hearing organ which contains specialized cells known as the stria vascularis by 14 days after birth. Degeneration of hair cells and spiral ganglion neurons along with obvious signs of inner ear dysfunction appeared by three weeks of age. Structural defects were also previously identified in the critical elements of zebrafish inner ear, including the otic vesicle (critical to ear development).

The findings in this report show that S1PR2 is an essential inner ear protein. The researchers said in the future, stimulating activity of this protein might reduce the harmful effects of antibiotics (e.g. gentamicin) on the ear’s hair cells, which are critical to hearing.

Others who took part in this work include: Kwanghyuk Lee, Xin Wang, Hang Dai and Anushree Acharya, all of Baylor; Rabia Faridi, Atteeq U. Rehman, Robert J. Morell, Inna A. Belyantseva and Thomas B. Friedman, all of the National Institute on Deafness and Other Communication Disorders (NIDCD) in Rockville, Maryland;  Muhammad Ansar, Syed Irfan Raza and Wasim Ahmad of Quaid-i-Azam University in Islamabad, Pakistan; Tanveer A. Qaiser and Zil-e-Huma Bashir of the University of the Punjab in Lahore, Pakistan; Rivka Isaacson of King’s College in London, UK; Dost Muhammad of Chandka Medical College in Larkana, Sindh, Pakistan; Rana Amjad Ali and Sheikh Riazuddin of the University of Lahore in Pakistan; Sulaiman Shams of Abdul Wali Khan University in Khyber Pakhtunkhwa, Pakistan; Muhammad Jawad Hassan of the National University of Science & Technology in Islamabad, Pakistan; Shaheen Shahzad of International Islamic University in Islamabad, Pakistan; and Joshua D. Smith, Deborah A. Nickerson and Michael J. Bamshad of University of Washington in Seattle. Grant funding for this work came from: the National Heart, Lung and Blood Institute (Grant U54HG006493); the NIDCD (Grants DC000039-18, R01DC011651 and R01DC003954); and the Higher Education Commission of Pakistan.