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Type I Usher Syndrome in the Acadian Population of Louisiana

Sevtap Savas, Ph.D.
Bronya J. B. Keats, Ph.D.

Clinical Characteristics of the Usher (USH) Syndromes. The Usher syndromes (USH) are a group of genetic diseases characterized by hearing loss and a degenerative retinal condition called retinitis pigmentosa (RP). There are three types of USH classified according to the severity and the age of onset of symptoms. Type I USH (USH1) is the most severe form of the disease. Profound hearing loss is present in USH1 infants before they learn to speak. Although hearing aids are not useful for USH1 patients, considerable success with early cochlear implants has been reported. RP begins in the first or second decade of life, as night blindness increases and field of vision decreases, and may progress to total blindness in early adulthood. In addition, USH1 patients have abnormalities in a component of the ear (the vestibular organ), which lead to balance problems. USH1 patients often have difficulty walking independently until they are at least 18 months of age.

USH2 and USH3 patients display similar but milder symptoms than USH1 patients. Hearing loss in USH2 is moderate to severe, and hearing aids are useful for USH2 patients. RP starts in the third or fourth decade of life, and vestibular function is normal. In USH3, the hearing loss is progressive, the age of onset of RP is variable, and some patients have balance problems.

Acadian patients with USH were first reported by Dr. H. W. Kloepfer and his colleagues in 1966. USH1 has a higher frequency in this population than in the general U.S. population. In addition, a few Acadians with USH2 have been reported.

Basic genetic facts about USH. The inheritance pattern for USH is autosomal recessive. Individuals with two defective (mutated) copies of the gene have USH; those with one normal copy and one defective copy are known as carriers. Around the world, the chance that an individual is a carrier is 1 in 70-100 individuals. (This is called the carrier frequency.) The frequency of USH patients is 2-6 per 100,000 individuals. (This is called the disease frequency). On average, 3-6% of deaf children have USH.

Why are frequencies of certain autosomal recessive genetic disorders like USH1 higher in Acadians? A higher disease frequency for autosomal recessive genetic disorders usually depends on the size and the structure of a population. Among 35,000 genes, each person carries perhaps a dozen or more defective genes, each defective gene being quite rare in the population. However, if marriages occur between individuals from the same small population because of historical, cultural, geographical, or other reasons, then the frequencies of some defective genes may increase in the next generations. Thus, the possibility that spouses carry the same defective gene is increased and, as a consequence, the frequency of children affected (children who have two defective copies) also increases. This phenomenon is known as a founder effect. The history of the Acadian people suggests that founder effects are the primary explanation for the relatively high frequency of USH1 in the Acadian population.

USH genes. USH is a genetically heterogeneous disease; that is, defects in different genes can cause the same disease. So far, six different genes for USH1 (USH1A-USH1F), three genes for USH2 and one gene for USH3 have been described. These genes were predicted by studying the DNA of several populations of people from around the world who suffer from USH. Analysis of USH1 members of Acadian families predicted that one of these genes (called USH1C) occurs on the short arm of chromosome 11.

USH1C gene and its defects in USH1 affected Acadians. Acadian patients have two copies of the defective USH1C gene. The presence of two copies of this defect in an individual means that the normal form of the protein coded by the USH1C gene is not produced. Lack of the normal form of this protein results in the individual having USH1. In late 2000, the USHIC gene was discovered, and the protein it encodes is called harmonin.

Although USH1 patients from other populations around the world can sometimes have mutated USH1C genes, so far the mutation originally found in Acadian patients (called the 216G>A mutation) is found in no other population. It is likely that this mutation occurred accidentally in the DNA of an ancestor of Acadian USH1C patients approximately 15 generations ago, while the Acadians were still in historic maritime Canada. A different mutation (called the 238-239insC mutation) common in USH1 patients with European and Pakistani origins was also found in two Acadian patients, but this mutation is thought to be only recently introduced into the Acadian population.

Once the molecular basis of a genetic disorder is discovered, identification of the gene and the mutations that cause a particular genetic disease is important for many reasons. In general terms, it is helpful to: (a) establish DNA tests useful to both confirm clinical diagnosis of the disease, and to develop carrier testing strategies, (b) predict the function of the protein and the way in which mutations affect function, and (c) develop treatment options, especially gene therapy.

Carrier and diagnostic testing for USH. Availability of routine and reliable DNA-based diagnostic and carrier identification tests for common mutations of a genetic disorder is one of the important outcomes of scientific research and should be considered in terms of its benefit to the public. In cases where there is no effective treatment, early detection of carriers and affected individuals is helpful for accurate genetic counseling. Individuals with a family history of a genetic disease (e.g. individuals with affected relatives and/or children) may consider obtaining genetic counseling to better understand their options. Accurate genetic counseling for affected individuals provides the opportunity to develop skills for coping with the disease both emotionally and physically, as well as seeking possible treatment options.

We are working on the development of a reliable DNA-based diagnostic strategy for the Acadian USH1C mutations (both the 216G>A and the 238-239insC mutations). This will allow not only early detection of carriers but also more accurate diagnoses of hearing impaired Acadian infants with USH1C syndrome. In addition, detection of USH syndrome during infancy may provide opportunities to delay or prevent the deterioration of vision that occurs in the young adult USH patient.

Selected References
Bitner-Glindzicz, M., Lindley, K. J., Rutland, P., Blaydon, D., Smith, V. V., Milla, P. J., Hussain, K., Furth-Lavi, J., Cosgrove, K. E., Shepherd, R. M., Barnes, P. D., O'Brien, R. E., Farndon, P. A., Sowden, J., Liu, X-Z., Scanlan, M. J., Malcolm, S., Dunne, M. J., Aynsley-Green, A., & Glaser, B. (2000). A recessive contiguous gene deletion syndrome causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nature Genetics, 26, 56-60.

Hereditary Hearing Loss Homepage: http://www.uia.ac.be/dnalab/hhh/

Hinderlink, J. B., Brokx, J. P., Mens, L. H., & van den Broek, P. (1994). Results from four cochlear implant patients with Usher's syndrome. Annals of Otology, Rhinology, and Laryngology, 103, 285-293.

Keats, B. J. B., & Corey, D. P. (1999). The Usher syndromes. American Journal of Medical Genetics, 89, 158-166.
Kimberling, W.J., & Moles, C. (1995). Clinical and molecular genetics of Usher Syndromes. Journal of the American Academy of Audiology, 6, 63-72.

Kloepfer, H. W., Laguaite, J. K., & McLaurin, J. W. (1966). The hereditary syndrome of congenital deafness and retinitis pigmentosa (Usher's syndrome). Laryngoscope, 76, 850-862.

Rushton, W. F. (1979). The Cajuns: From Acadia to Louisiana. New York: Farrar Straus Giroux.
Smith, J. H., Pelias, M. Z., Daiger, S. P., Keats, B., Kimberling, W., & Hejtmancik, J. F. (1992). American Journal of Medical Genetics, 43, 964-969.

Smith, R. J. H., Lee, E. C., Kimberling, W. J., Daiger, S. P., Pelias, M. Z., Keats, B. J. B., Jay, M., Bird, A., Reardon, W., Guest, M., Ayyagari, R., & Hejtmancik, J. F. (1992). Localization of two genes for Usher syndrome type 1 to chromosome 11. Genomics, 14, 995-1002.

Nouri, N., Risch, J., Pelias, M. Z., Litt, M., & Keats, B. J. K. (1994). Predicting the age of mutation for Usher syndrome type 1 in the Acadian population. American Journal of Human Genetics, 55 (Suppl.), A160.

Verpy, E., Leibovici, M., Zwaenepoel, I., Liu, X-Z., Gal, A., Salem, N., Mansour, A., Blanchard, S., Kobayashi, I., Keats, B. J. B., Slim, R., & Petit, C. (2000). A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nature Genetics, 26, 51-55.

Zwaenepoel, I., Verpy, E., Blanchard, S., Meins, M., Apfelstedt-Sylla, E., Gal, A., & Petit, C. (2001). Identification of three novel mutations in the USH1C gene and detection of thirty-one polymorphisms used for haplotype analysis. Human Mutation, 17, 34-41.

How to Learn More
Hereditary Hearing Loss Homepage: http://www.uia.ac.be/dnalab/hh/

Helen Keller National Center for Deaf-Blind Youth and Adults: http://hknc.org/UsherSynTblofCnts.htm

W. J. Kimberling and C. Moller (1995). Clinical and molecular genetics of Usher Syndrome. Journal of the American Academy of Audiology, 6, 63-72.

Robert J. Gorlin (1995). Genetic hearing loss associated with eye disorders. In Robert J. Gorlin, Helga V. Toriello, M. Michael Cohen, JR. (Ed.), Hereditary Hearing Loss and Its Syndromes (pp.105-118). New York, Oxford University Press.

About the Authors
Dr. Savas is a former post-doctoral research fellow at the Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA. Her main research interests include population diversity, molecular evolution, and molecular basis of Usher syndromes.

Dr. Keats is a Professor and Head of the Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA. She is also the Director of the Molecular and Human Genetics Center of Excellence, one component of which is the Center for Acadiana Genetics and Hereditary Health Care.

Contact the Authors
Sevtap Savas, Ph.D. 
Department of Genetics 
Louisiana State University Health Sciences Center
New Orleans, LA, USA 
Phone : (504) 568-8084
Fax : (504) 568-8500
E-mail: savas@mshri.on.ca

Bronya J. B. Keats, Ph.D. 
Department of Genetics 
Louisiana State University Health Sciences Center
New Orleans, LA, USA 
Phone : (504) 568-8088
Fax : (504) 568-8500
E-mail: bkeats@lsuhsc.edu