Учебники / Genetic Hearing Loss Willems 2004
.pdfx |
Contributors |
Paul Coucke, Ph.D. Connective Tissue Laboratory, Department of Medical Genetics, University Hospital Ghent, Ghent, Belgium
Cor W. R. Cremers, M.D. Department of Otorhinolaryngology, University Hospital Nijmegen, Nijmegen, The Netherlands
Else de Leenheer Department of Otorhinolaryngology, University Hospital Nijmegen, Nijmegen, The Netherlands
Koenraad Devriendt, M.D., Ph.D. Centre for Human Genetics, University of Leuven, Leuven, Belgium
Jill Dixon, Ph.D. School of Biological Sciences and Department of Dental Medicine and Surgery, University of Manchester, Manchester, England
Michael J. Dixon, B.D.S., Ph.D. Department of Dental Medicine and Surgery, School of Biological Sciences, University of Manchester, Manchester, England
Nathan Fischel-Ghodsian, M.D. Department of Pediatrics, Cedars-Sinai Medical Center and David Ge en School of Medicine at UCLA, Los Angeles, California, U.S.A.
Thomas B. Friedman, Ph.D. Laboratory of Molecular Genetics, Section on Human Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Paolo Gasparini, M.D. Division of Medical Genetics, Department of General Pathology, Second University of Naples and Telethon Institute of Genetics and Medicine, Naples, Italy
Richard J. Goodyear, D.Phil. School of Biological Sciences, University of Sussex, Brighton, England
Paul J. Govaerts, M.D., Ph.D. The Eargroup, Antwerp, Belgium
Andrew J. Gri th, M.D., Ph.D. Hearing Section and Section on Gene Structure and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Contributors |
xi |
Ronna Hertzano, B.Sc. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Egbert H. Huizing, M.D. Department of Otorhinolaryngology, University Hospital of Utrecht, Utrecht, The Netherlands
Tim Hutchin, Ph.D. Clinical Chemistry Department, Children’s Hospital,
Birmingham, England
William J. Kimberling, Ph.D. Center for the Study and Treatment of Usher Syndrome, Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska, U.S.A.
Mary-Claire King, Ph.D. Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington, U.S.A.
Shrawan Kumar, Ph.D. Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska, U.S.A.
Anil K. Lalwani, M.D. Division of Otology, Neurotology, and Skull Base Surgery, Department of Otolaryngology–Head and Neck Surgery, New York University, New York, New York, U.S.A.
Philippe P. Lefebvre, M.D., Ph.D. Department of Otorhinolaryngology, University of Lie`ge, Lie`ge, Belgium
P. Kevin Legan, Ph.D. School of Biological Sciences, University of Sussex, Brighton, England
Yan Li, M.D. Division of Otolaryngology, Department of Surgery, University of California–San Diego, La Jolla, California, U.S.A.
Anne C. Madeo, M.S. Hearing Section, National Institute on Deafness and Other Communication Disorder, National Institutes of Health, Rockville, Maryland, U.S.A.
Brigitte Malgrange, Ph.D. Center for Cellular and Molecular Neuroscience, University of Lie`ge, Lie`ge, Belgium
Alessandro Martini, M.D. Audiology Department, Ferrara University,
Ferrara, Italy
xii |
Contributors |
Wyman T. McGuirt, M.D. Molecular Otolaryngology Research Laboratories, Department of Otolaryngology–Head and Neck Surgery, University of Iowa, Iowa City, Iowa, U.S.A.
Anand N. Mhatre, Ph.D. Department of Otolaryngology, New York University, New York, New York, U.S.A.
Gustave Moonen, M.D., Ph.D. Center for Cellular and Molecular Neuroscience, University of Lie`ge, Lie`ge, Belgium
Robert J. Morell, Ph.D. Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Cynthia C. Morton, Ph.D. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Robert Mueller, M.D., F.R.C.P. Department of Clinical Genetics, St. James’s University Hospital, Leeds, England
Lina M. Mullen, Ph.D. Division of Otolaryngology, Department of Surgery, University of California–San Diego, La Jolla, California, U.S.A.
Kelly N. Owens, Ph.D. Department of Genome Sciences, University of Washington, Seattle, Washington, U.S.A.
Hong-Joon Park, M.D., Ph.D. Section on Gene Structure and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Shannon P. Pryor, M.D. Hearing Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Andrew P. Read, Ph.D., R.R.C.Path., F.Med.Sci. Department of Medical Genetics, St. Mary’s Hospital, Manchester, England
Guy P. Richardson, D.Phil. School of Biological Sciences, University of Sussex, Brighton, England
Contributors |
xiii |
Nahid G. Robertson, B.S. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.
Allen F. Ryan, Ph.D. Division of Otolaryngology, Department of Surgery, University of California–San Diego, La Jolla, California, U.S.A.
Julie M. Schultz, Ph.D. Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Hamish S. Scott, Ph.D. Department of Genetics and Bioinformatics Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Richard J. H. Smith, M.D. Molecular Otolaryngology Research Laboratories, Department of Otolaryngology–Head and Neck Surgery, University of Iowa, Iowa City, Iowa, U.S.A.
Karen Thompson, B.Sc. Molecular Medicine Unit, St. James’s University Hospital, Leeds, England
Lisbeth Tranebjærg, M.D., Ph.D. Department of Medical Genetics, Institute of Medical Biochemistry and Genetics, Wilhelm Johannsen Centre of Functional Genomics; Department of Audiology, Bispebjerg Hospital; and University of Copenhagen, Copenhagen, Denmark
Patrizia Trevisi, M.D. Audiology Department, Ferrara University, Ferrara,
Italy
Guy Van Camp, Ph.D. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
Kris Van Den Bogaert, Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
Hilde Van Esch, M.D., Ph.D. Centre for Human Genetics, University of Leuven, Leuven, Belgium
Lut Van Laer, Ph.D. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
xiv |
Contributors |
Sigrid Wayne, M.D. Molecular Otolaryngology Research Laboratories, Department of Otolaryngology–Head and Neck Surgery, University of Iowa, Iowa City, Iowa, U.S.A.
Edward R. Wilcox, Ph.D. Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, U.S.A.
Patrick J. Willems, M.D., Ph.D. GENDIA, Antwerp, Belgium
1
Normal Development of the Ear in the Human and Mouse
Lina M. Mullen, Yan Li, and Allen F. Ryan
University of California–San Diego, La Jolla, California, U.S.A.
I.INTRODUCTION
The development of the normal ear is an extremely complex process, owing to the diversity of tissues and cells that are present in the ear compared to some other organs. The outer, middle, and inner ear consist of several di erent tissues, each of which in turn contains highly diverse cell types. The formation and di erentiation of these cell types must occur in a precisely coordinated manner, to result in the intricate structures and complex functional capabilities of the ear. The number of genes that are involved in ear development presumably reflects this tissue and cellular diversity. It is not unreasonable to assume that the coordinated expression of thousands of genes occurs during the development of the ear. Among these, it seems likely that hundreds of genes play a direct role in regulating inner ear development, and the number may be even greater (91,112). These genes provide a major substrate for inherited hearing loss. Indeed, mutations that disturb the normal process of ear development appear to account for the majority of inherited deafness.
To understand inherited hearing loss related to defects in the formation of the ear, it is necessary to first understand the normal process of inner-ear development. This includes the anatomical development of the outer, middle, and inner ears, as well as the appearance and maturation of peripheral auditory function. It is the purpose of this chapter to review this development. Finally, the patterns of gene expression that occur during ear development are ultimately responsible for its anatomical and functional
1
2 |
Mullen et al. |
maturation. While a complete review of developmental gene expression in the ear is beyond the scope of this chapter, we describe some general patterns of expression that have implications for the development of the ear and that can provide insights into genetic deafness by highlighting critical molecular events and processes.
While ear development has been studied in a wide variety of species, this review will concentrate on that of the human and mouse. Normal ear development is obviously of critical importance to our understanding of inherited hearing loss in humans. In addition, as the most extensively characterized mammalian animal model for genetics, and the mammalian species in which genetic manipulation is most easily performed, the mouse is the animal model most relevant to inherited hearing loss in humans. The time course of development in these two species is of course very di erent. Human embryonic development is prolonged, because of the larger size of the species, because human infants are more functional at birth, and perhaps because of the higher degree of complexity of the human brain. For example, in man, the embryo progresses from stage 9, at which the inner ear begins development, to stage 23, at which the cochlea has developed 1 1/2 turns, over the period from 3 to 8 postconception weeks (83). Thus the human ear develops over a period of months, and even years, and most of the developmental events that occur in utero are defined by the gestational week in which they occur. In contrast, murine embryonic development is a very rapid process, because the mouse is a small mammal in which the young are born in a very immature state. The mouse embryo undergoes the progression from stages 9 to 23 over the period from 9 to 16 days postconception (dpc) (115). In this species therefore, the process of ear development occurs in a matter of weeks, and with parturition at around 20 dpc a substantial amount of ear development occurs after birth. Developmental events are thus defined by the gestational day or fraction of a day. These di erences must be taken into account when comparing events as they occur in the two species.
II.THE ANATOMICAL DEVELOPMENT OF THE OUTER, MIDDLE, AND INNER EAR
The ear arises during early embryonic development, soon after the central nervous system begins to form, with the temporally coordinated formation of the tissue precursors of the outer, middle, and inner ear. The tissues that make up these three divisions of the ear are derived from a number of di erent embryonic sources. The divisions of the ear must develop in parallel, and in precise orientation, for normal hearing to arise.
Development of the Ear |
3 |
A.Development of the External Ear
1.Human
In humans, the auricle develops from the ectoderm and underlying mesoderm of the first and second branchial arches, beginning as tissue condensations in the fourth fetal week (Fig. 1). Shaping of the external ear begins with the formation of six distinct hillocks on the first and second arches located ventrally on the embryo during the fifth week (1,127). Cartilage formation begins during the sixth week, and the auricle moves dorsolaterally into its adult position during the seventh week (16,41). The auricle achieves its mature shape by about 20 weeks of development (43). After birth, the auricle increases in size, and the underlying cartilage becomes more dense, until the adult size and consistency is reached by 8–9 years. However, the auricle increases in length throughout life (89).
The external auditory canal forms from the first branchial groove, between the first and second arches (44,88,94). During the fourth and fifth fetal week, this groove deepens to abut the developing tubotympanic cavity for a brief interval (43). However, by the sixth week, proliferating mesenchymal tissue separates the developing middle and external ears again (80). Whether the transient contact between the developing external and middle ears serves an inductive purpose is not clear. The meatus deepens again beginning at the eighth week, but does not remain an entirely open cavity. As the canal deepens by the proliferation of ectodermal cells, the cells at the medial end do not cavitate. By the ninth week, a solid cylinder of ectodermal cells known as the medial ectodermal plate fills the medial aspect of the deepening meatus (9). This remains intact until the twenty-
Figure 1 Development of the external ear in humans, tracing the development of adult structures from primordia on the first and second branchial arches. (Adapted from Ref. 9.)