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ODHHS Information
Current Progress in Finding Genes
Involved in Hearing Impairment
(Source: Boystown Research Registry)
Heredity is the most important factor in the cause of significant hearing impairment in humans. It has been estimated that well over half of all cases of childhood deafness have a genetic cause. A better understanding of the nature of the genes which cause these hearing problems promises to improve our diagnostic abilities and will lay the foundation for research into more effective methods of treatment and remediation.
The problems surrounding the study of hereditary deafness are rather daunting. The number of genes involved is large (McKusick´s catalogue lists several hundred syndromes that have hearing impairment as one component) and many cases are due to different genes. But we don´t yet have the clinical tools to separate cases into fully useful categories.
Since families used for research must be pooled and, if families with different types of hereditary hearing impairments are included in the same study, obvious correlations between the gene and the hearing impairment may not be noticed. As a consequence, progress in the field of hereditary deafness has proceeded more slowly than progress in other areas of human genetics. Nonetheless, research into the different types of genetic hearing impairment has progressed significantly over just the past few years. Several genes have been localized to specific chromosomes and in some cases the actual gene responsible has been identified, cloned and its function determined. Many of these are listed in Table 1 and discussed in further detail below.
Usher Syndrome (Hearing impairment with retinitis pigmentosa). The surprising finding about Usher Syndrome is that so many different genes seem to be involved. The existence of five different genes have been identified by virtue of being in five different chromosomal regions (1-5) and there is evidence that there may be an additional two more genes, making a total of seven Usher genes in all. One of the genes located this year causes a progressive hearing impairment (1). This kind of Usher syndrome previously had been called type III and the only families found so far with type III live in Finland. It is probably only a matter of time until similar families in other parts of the world are found. One gene for Usher syndrome type Ib (3) is believed to code for a myosin-like gene which may be needed for normal stereociliary function. This finding suggests that there may be a group of hearing impairment disorders which specifically involve stereociliary proteins, of which the Usher syndromes are one group. Furthermore, now that one of the Usher genes has been identified, some of the complexity of diagnosis will be simplified with the eventual introduction of molecular methods of diagnosis. It is important to state the shaker-1 mouse is a model for Usher 1b and may be helpful in further investigation into the expression of the gene and into method of treatment.
Waardenburg Syndrome (Hearing impairment with heterochromia [two colors of eyes], poliosis [white forelock of hair], and telocanthus [wide spaced eyes]). Two Waardenburg syndrome genes have been located and identified. One is on chromosome 2 and is called PAX3 (6). The PAX3 gene is one of several genes which control an aspect of development of the face and inner ear. The second gene found on chromosome 3 is called MITF and also controls development of the ear and hearing (7).The functions of these genes are now being intensively studied in an effort to better understand how they operate in controlling the normal growth of ear and development of hearing. Such information will have a tremendous impact on our understanding of why persons with Waardenburg syndrome sometimes develop hearing problems.
Gene Localization and Identification of Genes Causing Hearing Impairment in Humans
Disorder Inheritance Linkage Gene Reference
Usher Syndrome Type III AR 3q 1
Usher Syndrome Type Ia AR 14q 2
Usher Syndrome Type Ib AR 11q13 HHMM7 3
Usher Syndrome Type Ic AR 11p13 4
Usher Syndrome Type IIa AR 1q41 5
I AD 2q 3 6
I AD 3p M ITF 7
Alport Syndrome XLR X q C O L4A5 8
Alport Syndrome AD 2 q C O L4A3 9
Alport Syndrome AD 2q C OL4A4 9
Branchio-Oto-Renal Syndr om e A D 8 q 0
Stickler Syndrome AD 12q COL2A1 11
Stickler Syndrome AD 6p COL11A2 12
Crouzon Syndrome AD 10q F 13
Treacher-Collins Syndr ome A D 5q 14
Norries Syndrome XL R Xp NPD 15
Stapes Fixation with Perilymphatic XLR q BRN 1 16
Neurofibromatosis II AD 22q 17
Albinism-Deafness XLR Xq 18
Non-syndromic recessive AR 11q 19
Non-syndromic recessive AR 13q 20
Non-syndromic recessive AR 17p 1
Progressive loss, high frequency AD 1p 22
Progressive loss, low frequency AD 5q 23
Osteogenesis Imperfecta AD 17 q A1 24
Osteogenesis Imperfect a AD 5 p COL1 A2 24

Alport Syndrome (Hearing impairment with nephritis). The genes for Alport syndrome have been located and identified. Most, but not all, Alport syndrome families show X-linked inheritance and thus men are usually more severely affected (8). The gene on the X-chromosome has been identified as COL4A5, a gene which codes for one form of collagen. This collagen forms part of the connecting structure within the inner ear and the kidney. When the gene is changed, that connection appears to be more fragile, and progressive kidney disease and progressive hearing impairment results. Changes in two other collagen genes, COL4A3 and COL4A4, have also been found to cause Alport syndrome (9). These cases are inherited as autosomal recessive and not X-linked. There may yet be an autosomal dominant form whose gene remains to be identified.
Branchio-Oto-Renal Syndrome (Hearing impairment with earpits and renal anomalies). It is believed that this may be the same as what is more commonly referred to as the earpits-deafness syndrome. The gene for this disorder has been found on chromosome 8 (10). The region containing the gene has been pinpointed to a small section but actual identification has not yet been possible. French researchers using a patient with BOR and a rearranged chromosome 8q have identified a Yeast Artificial Chromosome that must contain the gene. Rapid progress towards the cloning is now expected.
Stickler Syndrome (Hearing impairment, detached retina, myopia, and micrognathia). The gene causing Stickler syndrome has been found to be a collagen gene, COL2A1 on chromosome 12 (11). A second gene has been identified on chromosome 6 and it is believed that this may be due to changes in another collagen gene, COL11A2 (12). Many persons with Stickler syndrome have a progressive hearing impairment.
Osteogenesis Imperfecta (Fragile bones, sometimes occurs with hearing impairment). There are several genes implicated in Osteogenesis Imperfecta (OI). While the striking finding of OI is brittle bones which break easily, hearing impairment is a common component of some types. Four subtypes of OI have been described based upon clinical findings. However, not only is there clinical variation within an OI type and between OI types (e.g., although blue sclerae is common in Type I and also is seen in Type IV, some indi-viduals with Type I or Type IV have normal sclerea), but there is also genetic heterogeneity within types (e.g., Type I can be caused by mutations in COL1A1 on chromosome 17q21.31-22 and COL1A2 on chromosome 7q22.1) (24).
Crouzon Syndrome (Craniosynostosis). The major clinical manifestations of Crouzon syndrome are due to premature fusion of the cranial sutures. Hearing impairment is a common complaint. The gene for Crouzon has been identified as the fibro-blast growth factor gene on chromosome 10q (13).
Treacher Collins Syndrome (Craniofacial anomalies). Treacher-Collins syndrome is a defect of craniofacial morphogenesis which is associated with asymmetric facies, cleft palate, and hearing impairment. The gene for this disorder has not been cloned but it has been localized to chromosome 5q (14).
Norries Syndrome (Exudative vitreoretino-pathy with hearing impairment). The gene for Norries syndrome has long been known to be on the X-chromosome. Just recently, it location was re-fined to Xp11 and the gene was identified (called NDP) (15). It was hypothesized that the NDP mole-cule may be involved in a pathway that regulates neural cell differentiation and proliferation.
X-Linked Hearing Impairment. X-linked deafness does not cause a substantial number of cases of hearing impairment. Because of the distinctive pattern of inheritance, however, several large families have been found and subsequently studied. One type of X-linked deafness is associated with stapes fixation and perilymphatic gusher. Either this or another gene near it has been identified as the gene for BRN1, a probable developmental gene whose function is not known (16). It is probable that there is more than one gene on the X-chromosome causing non-syndromic hearing impairment and likely that the situation will become more confused before it clarifies.
Neurofibromatosis II (NF2) is characterized by bilateral tumors of the VIIIth cranial nerve. The acoustic neuroma results in significant hearing impairment. The gene is inherited as an autosomal dominant condition. The gene responsible for NF2 has been identified and may represent a novel class of tumor suppressor genes. It is located on chromosome 22q (17).
Other syndromes. There are a few other syndromes associated with deafness that have been subjects of positional cloning experiments. They are listed in the table for the sake of completeness but, because they are rare (dominant albinism deafness, for example, has only been described in one family[18]), they won´t have any general interest until their respective genes are identified.
Non-syndromic hearing impairment. When hearing impairment occurs in association with no other physical findings, it is called non-syndromic. The locations of several genes, both dominant and recessive, have been located. Three recessive genes have been located, one on chromosome 11q (19), one on chromosome 13q (20), and one on chromosome 17p (21). The total number of recessive genes is not known, but these results represent significant advances. In addition, two genes causing dominant progressive hearing impairment have been located, one on chromosome 1p (22) and another on chromosome 5q (23).
The number of known genes causing hearing impairment is growing and our expectation is that many more will be uncovered in the future. The information coming from genetic research is beginning to impact in two distinct ways. First, it is possible now to talk about the use of molecular techniques in the diagnosis of hearing impairment disorders. Otolaryngologists and audiologists will soon have a sophisticated means of diagnosing many of the heritable causes of hearing impairment. It is to be expected that clinical researchers will begin to compile their experiences in treatment and rehabilitation and certainly this will lead us to more effective ways of helping people with hearing impairments. Second, our understanding of how the hearing sense develops and is maintained is increasing by leaps and bounds. Basic information of that sort must influence how we think about the normal process of hearing and should lead us to a more complete understanding of that complex process.
by William J. Kimberling, Ph. D.
  1. Sankila, E.-M, et al., Am J Hum Genet. 55:A15, 1994.
  2. Kaplan, J, et al., Genomics 14:979, 1992.
  3. Kimberling WJ, et al., Genomics 7:245, 1990.
  4. Smith, RJH, et al., Genomics 14:995, 1992.
  5. Kimberling, WJ, et al., Genomics 14:988, 1992.
  6. Foy, C, et al. Am. J. Hum. Genet. 46:1017, 1990.
  7. Hughes, AE, et al. Nature Genet. 7:509, 1994.
  8. Barker, DF, et al., Science 248:1224, 1990.
  9. Mochizucki, T, et al., Nature Genet. 8:77, 1994.
10. Smith, RJH, et al., Genomics 14:841, 1993.
11. Ahmad, NN, et al., Proc. Natl. Acad. Sci. 88:6624, 1991.
12. Brunner, HG, et al., Hum. Molec. Genet. 3:1561, 1994.
13. Reardon, W, et al., Nature Genet. 8:98, 1994.
14. Dixon J, et al., Am J Hum Genet. 55:372, 1994.
15. Berger, W., et al., Hum Mol Genet. 1:461, 1992.
16. Brunner, HG, et al., Hum Genet. 80:337, 1988.
17. Rouleau, GA, et al., Nature 363:515, 1993.
18. Shiloh, Y et al., Am J Hum Genet. 47:20, 1992.
19. Guilford, P, et al., Hum Mol Genet. 6:989, 1994.
20. Guilford, P, et al., Hum. Genet. 6:24, 1994.
21. Friedman, TB, et al., Am J Hum Genet. 55:A15, 1994.
22. Couke, P, et al., New Engl. J. Med. 331:425, 1994.
23. Leon, PE, et al., Proc. Natl. Acad. Sci., USA 89:5181, 1992.
24. Retief, E, et al., Hum Genet. 69:304, 1985.

Date Originally Created: Spring of 1995.
The information presented here first appeared in publications of the Boys Town National Research Register for Hereditary Hearing Loss, the National Institute on Deafness and Other Communication Disorders (NIDCD), Hereditary Hearing Impairment Resource Registry (HHIRR), or the Boys Town Research Registry for Hereditary Hearing Loss.
The Boys Town Research Registry for Hereditary Hearing Loss
The Boys Town Research Registry for Hereditary Hearing Loss (Registry) is designed to foster a partnership between families, clinicians and researchers in the area of hereditary hearing loss/deafness through three primary functions. First, the Registry disseminates information to professionals and families about clinical and research issues related to hereditary deafness/hearing loss. Second, the Registry collects information from individuals interested in supporting and participating in research projects. This information is used to support the third function of the Registry - matching families with collaborating research projects.
For more information, contact:
Research Registry for Hereditary Hearing Loss
555 N. 30th Street
Omaha, NE 68131
800 320-1171 (V/TDD)
402 498-6331 (FAX)