DEAFNESS: GENETICS AND PHYSIOLOGICAL MECHANISMS

Surprisingly, up to the beginning of the 90’s, very little was known about the cochlea (figure 1), the auditory sensory organ which breaks down sound messages and transforms them into electrical signals which are sent to the brain. Physicists had been curious about its enigmatic properties from the beginning of the 19th century and had proposed some theoretical explanations of its functioning. In contrast, the cellular and molecular mechanisms underlying its physiological properties were entirely unknown. Hearing is achieved by a mere 3000 sensory cells, the inner hair cells. This small number of cells (the retina, for example, contains some 120 million photoreceptor cells) implied that the cochlea could not be studied by biochemical or classical molecular biology methods. In order to tackle this issue, Christine Petit decided to resort to a genetic approach, i.e. an approach in which the number of cells involved does not matter.

Genes for deafness
In order to discover the defective genes underlying deafness, Christine Petit first had to overcome a particular obstacle to the genetic study of this handicap. A gene implicated in a disease or a handicap is identified by studying affected families and following its transmission from one generation to the next. However, in developed countries, the deaf, like their children, tend to inter-marry. Several deafness genes can therefore be present in the same family and it is difficult, or even impossible, to distinguish the hearing impairment due to the various genes, i.e. to a gene inherited from the father or a gene transmitted by the mother. Christine Petit overcame this problem by studying deaf families living in geographically isolated regions around the Mediterranean. Within these geographic isolates, generally founded by a small number of individuals, deafness is usually caused by a single genetic defect. This approach allowed her to map the first genes responsible for children deafness on the human chromosomes. She then identified the defective genes in sixteen forms of deafness. Furthermore, she demonstrated that, unexpectedly, one of these, which codes for connexin-26, is responsible for half the cases of congenital severe to profound deafness in Mediterranean countries. As a result, the connexin-26 gene is one of the most commonly mutated genes in humans.

Since Christine Petit first paved the way, forty genes implicated in deafness have been discovered, almost half by her team. “When I started this research”, she emphasises, “childhood deafness was known to be mainly sensorineural and often due to cochlear defects. However, a large number of cases were mistakenly attributed to previous unnoticed infections”. Today, thanks to Christine Petit’s research, we know that heredity plays a major part in the aetiology of childhood deafness in developed countries. Due to the discovery of genes which are defective in deafness, molecular diagnosis has been developed and different forms of inherited deafness clinically characterised, both of which have considerably improved the quality of genetic counselling for families with a deaf member.

Functioning of the inner ear
While identifying the pieces of this genetic puzzle, Christine Petit’s research aimed at understanding how the proteins encoded by the discovered genes work together in the development and functioning of the inner ear. Using transgenic mice as animal models of human deafness, she elucidated different mechanisms accounting for hereditary hearing impairment. Thus, we now know that many forms of deafness are due to malfunctioning of the sensory cell per se. The hair bundle (figure 2), the cellular compartment in which the acoustic signal is transformed into an electrical signal, is often the subcellular structure affected. In other instances, the defect is due to abnormalities of the structure of the tectorial membrane (which transfers the energy of the auditory stimulus to the hair bundle, figure 1B), or of ionic homeostasis, in particular that of potassium, which conveys the transduction current. Finally, it appears that in the most common form of congenital deafness in children, the defect in the encoded protein, connexin-26, affects the activity of several cell types in the cochlea, including cells in which it is not expressed.

Hair bundle
Combining the genetics results and those obtained by using other experimental approaches, Christine Petit showed how various molecules act together to establish and/or maintain a variety of processes within the cochlea. Let us consider as an example, the cohesion of the stereocilia (the rigid microvilli making up the hair bundle; see figure 2), which is essential for the proper functioning of the hair bundle. Christine Petit and her collaborators demonstrated three mechanisms which operate sequentially during the development and maturation of the stereocilia. The first, which prevents fragmentation of the hair bundle during its initial growing stage, involves five proteins that are defective in five different forms of Usher syndrome type I (in which deafness is associated with blindness). The second enables the precise alignment of the stereocilia within the hair bundle by connecting their bases by fibrous links made up of proteins encoded by the genes which are defective in Usher syndrome type II. The third prevents the disconnection of the stereocilia and protects the hair bundle from mechanical sound stress by holding their tips together in a previously unnoticed acellular “cap”. This cap is also composed of a protein encoded by a gene which is defective in one form of deafness.

Christine Petit’s research, based on genetics, then strengthened by a multidisciplinary approach, enabled her to succeed in deciphering many of the cellular and molecular mechanisms ensuring the functioning of the cochlea, abnormalities of which cause a loss of auditory acuity. Her advances pave the way to the development of a therapeutic approach for hereditary deafness, for which no treatment is currently available.

With the resources placed at her disposal by the 2006 Louis-Jeantet Prize for Medicine, Christine Petit intends to extend her study of the cellular and molecular mechanisms of hearing and of its dysfunction in humans to the auditory pathways. By the in vivo identification and selective ablation of different neurons of mouse brainstem nuclei and of their connections, her objective is to gain a significant insight into their role in the coding of auditory information.

Figure 1.

A. Schematic representation of the human ear
The ear is made up of the external ear, the middle ear (with the three ossicles, i.e. incus, malleus, stapes), and the inner ear. The latter is comprised of the cochlea, devoted to sound analysis, and the vestibule, which responds to accelerations of the head. The inner ear is filled with fluids, the endolymph (light blue) and the perilymph (dark blue).

B. Schematic representation of a cross-section through the cochlear duct
Different types of epithelia surround the scala media (filled with endolymph), including the auditory sensory epithelium, the organ of Corti which is comprised of two types of sensory cells (in yellow), the inner hair cells (IHC, one row) and the outer hair cells (OHC, three rows), and various types of supporting cells (in green). The latter includes the pillar cells (p), Deiters’ cells (d), Hensen’s cells (h). Other abbreviations: (c) Claudius’ cells, (i) interdental cells, (sp) spiral prominence.

Figure 2.

Hair bundle disorganisation in a mouse model for Usher I syndrome. 
Schematic representation of the organ of Corti. In the insert, a hair bundle (A).
Scanning electron microscopy of a differentiating hair bundle in a wild-type mouse at postnatal day five (P5) (B), at birth (P0) (C), and (D) in a mouse mutant defective for harmonin encoded by a gene causative for Usher I syndrome. The hair bundle is disrupted in two fragments in harmonin-/- mice. Abbreviations: IHC: inner hair cell, OHC: outer hair cell.

Professor Christine PETIT
Professor au Collège de France
Inserm U587 « Genetics of Sensory Deficits »
Department of Neuroscience
Pasteur Institute
Rue du Dr Roux 25
F – 75724 PARIS CEDEX 15

Phone: +33 1 45 68 88 90 / 88 50
Fax: +33 1 45 67 69 78
E-mail:  cpetit@pasteur.fr