The Usher Syndromes

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 89:158–166 (1999) REVIEW

The Usher Syndromes

BRONYA J.B. KEATS* AND DAVID P. COREY

Mutations in the gene (MYO7A) encoding myosin-VIIa, a member of the large superfamily of myosin motor proteins that move on cytoplasmic actin filaments, and in the USH2A gene, which encodes a novel protein resembling an extracellular matrix protein or a cell adhesion molecule, both cause Usher syndrome (USH), a clinically heterogeneous autosomal recessive disorder comprising hearing and visual impairment. Patients with USH1 have severe to profound congenital hearing impairment, vestibular dysfunction, and retinal degeneration beginning in childhood, while those with USH2 have moderate to severe hearing impairment, normal vestibular function, and later onset of retinal degeneration. USH3 is characterized by progressive hearing loss and variable age of onset of retinal degeneration. The phenotype resulting from MYO7A and USH2A mutations is variable. While most MYO7A mutations cause USH1, some cause nonsyndromic hearing impairment, and one USH3 phenotype has been described. USH2A mutations cause atypical USH as well as USH2. MYO7A is on chromosome region 11q13 and USH2A is on 1q41. Seven other USH genes have been mapped but have not yet been identified. USH1A, USH1C, USH1D, USH1E, and USH1F have been assigned to chromosome bands 14q32, 11p15.1, 10q, 21q21, and 10, respectively, while USH2B is on 5q, and USH3 is at 3q21-q25. Myosin VIIa mutations also result in the shaker-1 (sh1) mouse, providing a model for functional studies. One possibility is that myosin-VIIa is required for linking stereocilia in the sensory hair bundle; another is that it may be needed for membrane trafficking. The ongoing studies of myosin-VIIa, the USH2A protein, and the yet to be identified proteins encoded by the other USH genes will advance understanding of the Usher syndromes and contribute to the development of effective therapies. Am. J. Med. Genet. (Semin. Med. Genet.) 89:158–166, 1999. ᮊ 2000 Wiley-Liss, Inc.

KEY WORDS: hearing impairment; pigmentary retinopathy; myosin VIIa; genetic heterogeneity; clinical heterogeneity

INTRODUCTION a child may be diagnosed as having a trophy of the retina in 1858, and nonsyndromic congenital hearing im- Charles Usher, a British ophthalmolo- The Usher syndromes (USH) are a pairment, with USH not being consid- gist, provided extensive clinical docu- group of clinically variable and geneti- ered until the onset of vision loss in the mentation of affected individuals [Gor- cally heterogeneous autosomal recessive second decade. The prevalence of USH lin et al., 1995]. In particular, Usher disorders. They are characterized by is estimated to be between 1/16,000 [1914] emphasized the autosomal reces- congenital sensorineural hearing loss and 1/50,000 based on studies in Scan- sive pattern of inheritance and sug- and pigmentary retinopathy, which dinavia [Hallgren, 1959; Nuutila, 1970; gested the existence of at least two usually manifests in late childhood or clinical types of USH based on the de- adolescence and may lead to total blind- Grondahl, 1987; Rosenberg et al., gree of hearing impairment and the age ness. Unless there is an affected relative, 1997], Colombia [Tamayo et al., 1991], the United Kingdom [Hope et al., of onset and progression of the visual 1997], and the United States [Bough- loss. Dr. David P. Corey is a neurobiologist at man et al., 1983]. USH is reported to Massachusetts General Hospital, a professor at Harvard Medical School, and an account for between 3% and 6% of the PHENOTYPE Investigator of the Howard Hughes congenitally deaf population [Vernon, Medical Institute. He studies the physiol- ogy and cell biology of sensory transduc- 1969], about 18% of those with retinitis The two types of USH described by tion by hair cells of the auditory and ves- pigmentosa, and more than 50% of the Usher [1914] are the forms that are tibular systems. Dr. Bronya J.B. Keats is a professor deaf-blind population [Boughman et most widely recognized clinically. Pa- of genetics and the director of the Mo- al., 1983]. The significance of advanc- tients with Usher syndrome type I lecular and Human Genetics Center at ing understanding of the genetic defects (USH1) have severe to profound con- Louisiana State University Health Sci- ences Center. Her research interests in- responsible for the single, major cause genital hearing impairment, vestibular clude the identification and character- of deaf-blindness and relieving the tre- dysfunction, and retinal degeneration ization of genes involved in the hereditary ataxias and hearing impair- mendous personal burden imposed by beginning in childhood, while those ment, especially in the Acadian popula- loss of both vision and hearing cannot with type II (USH2) have moderate to tion of southwestern Louisiana. be underestimated. severe hearing impairment, normal ves- *Correspondence to: Department of Biometry and Genetics, LSU Medical The German ophthalmologist Al- tibular function, and later onset of reti- Center, 1901 Perdido Street, New Or- brecht von Graefe described the asso- nal degeneration. Detailed diagnostic leans, LA 70112. E-mail: [email protected] ciation of congenital hearing impair- criteria were defined by the Usher Syn- ment and progressive pigmentary dys- drome Consortium [Smith et al., 1994]. © 2000 Wiley-Liss, Inc. REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 159

The relative percentages of USH1 and due to progressive degeneration of rod ited to the posterior fossa or auditory USH2 vary among studies but recent photoreceptor cells, but it may not be- and visual systems [Schaefer et al., reports suggest that type II is more come a serious problem until the third 1998]. common than type I [Fishman et al., or fourth decade. However, abnormali- 1983; Kimberling et al., 1991; Hope et ties in an electroretinogram (ERG) may GENE MAPPING al., 1997; Rosenberg et al., 1997]. A be detected in early childhood [Young AND IDENTIFICATION third type of Usher syndrome (USH3) et al., 1996]. Thus, an ERG should be is characterized by progressive hearing done at an early age and repeated at The Hereditary Hearing Loss Home loss and variable age of onset of retinal regular intervals for any hearing im- Page (URL: http://dnalab-www.uia. degeneration [Davenport and Omenn, paired child who may be at risk for ac.be/dnalab/hhh) provides a compila- 1977; Pakarinen et al., 1995]. USH. Early diagnosis of USH would tion of all mapped loci and identified The typical audiogram for type I enable an extended time to prepare for genes for phenotypes involving hearing patients shows no detectable hearing both the physical and emotional impact loss [Van Camp and Smith, 1999]. Syn- across all frequencies although there of the gradual visual loss [Miner, 1995; dromic hearing impairment tends to be may be some residual low frequency Tamayo et al., 1997]. less genetically heterogeneous than hearing (<250 Hz) detectable at ampli- Vestibular dysfunction, in addition nonsyndromic. However, the number tudes of 80–100 dB. In general, hearing to degree of hearing impairment, dis- of genes that have so far been mapped aids are not helpful for these patients, tinguishes USH1 from USH2. Chil- for USH1 is six. These six genes are on but they receive measurable benefit dren with USH1 show delayed motor chromosome arms 14q [Kaplan et al., from cochlear implantation [Hinderlink development because they cannot sense 1992], 11q [Kimberling et al., 1992], et al., 1994; Young et al., 1995]. In gravity [Mo¨ller et al., 1989; Smith et al., 11p [Smith et al., 1992a], 10q [Wayne contrast, the typical audiogram for type 1994], and show no nystagmus in re- et al., 1996], 21q [Chaib et al., 1997], II patients slopes from a moderate hear- sponse to ice-water caloric stimulation. and on chromosome 10 [Wayne et al., ing loss in the low frequencies down to On the other hand, USH2 patients 1997]. USH2 loci have been assigned to a severe loss in the high frequencies, show normal motor development and chromosome arms 1q [Kimberling et and appropriate hearing aids are usually brisk nystagmus. al., 1990, Lewis et al., 1990] and 5q beneficial. Unlike USH3, the degree of Other clinical findings that have [Pieke-Dahl et al., 1998], and Sankila et loss does not change over time with ei- been reported in USH patients include al. [1995] localized a gene for USH3 to ther USH1 or USH2. olfactory loss [Zrada et al., 1996], struc- 3q. Thus, mutations in nine different Pigmentary retinopathy is the tural abnormalities of nasal cilia [Arden genes cause USH, and unlinked families clinical finding that provides a defini- and Fox, 1979; Marietta et al., 1997], of each type suggest at least three more tive diagnosis of USH and distinguishes and decreased sperm motility [Hunter [Pieke Dahl et al., 1993, 1996, 1998]. it from nonsyndromic sensorineural et al., 1986]. Hunter et al. [1986] also hearing impairment. Night blindness is found a high proportion of abnormal often the first symptom of the retinal axonemes in retinal photoreceptor cells Thus, mutations in nine degeneration. A comprehensive oph- and Berson and Adamian [1992] ob- different genes cause USH, thalmological examination may provide served that most of the connecting cilia of photoreceptors in the macula were and unlinked families of abnormal. Biochemical studies suggest each type suggest at least Pigmentary retinopathy is that USH1 patients have decreased levels of phospholipids in red blood cells three more. the clinical finding that and plasma, but USH2 patients have normal levels [Bazan et al., 1986; provides a definitive USH1A Maude et al., 1998]. In general, tempo- diagnosis of USH and ral bone histopathologic studies of all USH1A was mapped to chromosome distinguishes it from USH types have shown extensive de- band 14q32 by analysis of families from generation of the hair cells of the organ the Poitou-Charentes region of France nonsyndromic sensorineural of Corti and spiral ganglion cells with [Kaplan et al., 1992]. The interval con- hearing impairment. atrophy of the stria vascularis [Belal, taining the gene was refined by Larget- 1975; Cremers and Delleman, 1988; Piet et al. [1994], who also demon- Nadol, 1988a,b; Shinkawa and Nadol, strated genetic heterogeneity among valuable prognostic information [Fish- 1986; van Aarem et al., 1995a]. Neu- French USH1 families from different man et al., 1995; Edwards et al., 1996, roimaging studies showed a significant geographic regions. A candidate gene, 1998], although van Aarem et al. decrease in intracranial volume and in the human homologue of the gene en- [1995c] reported considerable variabil- size of the brain and cerebellum sug- coding the echinoderm microtubule- ity in visual acuity among Dutch USH2 gesting that the disease process in USH associated protein (EMAP), was isolated patients. Visual loss gradually increases involves the entire brain and is not lim- from the USH1A region but was ex- 160 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) REVIEW cluded as the disease gene [Eudy et al., genes. This hypothesis was proven to myosin-VIIa gene, but the alleles with 1997]. be correct when Gibson et al. [1995] mutations in important conserved do- showed that the sh1 gene encodes myo- mains have the least amount of myosin- sin-VIIa, and Weil et al. [1995] quickly VIIa protein and the most severely USH1B and Myosin-VIIa found mutations in human MYO7A in compromised hair cells, suggesting that After the initial demonstration of link- USH1B patients. nonfunctional myosin-VIIa is more age of USH1B to markers at 11q13.5 in Myosin-VIIa was first identified in rapidly degraded in cells [Mburu et al., families from the United States, Swe- a human colon carcinoma cell line [Be- 1997; Hasson et al., 1997a]. Most of the den, Ireland, South Africa, and Britain ment et al., 1994], and was found also alleles display some disorganization of [Kimberling et al., 1992; Smith et al., in hair cells of the amphibian inner ear the sensory hair bundle, and while ste- 1992a], Bonne´ Tamir et al. [1994] re- [Solc et al., 1994]. Cloning of the full- reocilia may still show the staircase ar- fined the candidate region by analysis of length human and mouse myosin-VIIa rangement of heights, the bundles seem a large Samaritan kindred. The physical cDNAs demonstrated a large protein of fragmented into patches with a few ste- mapping of the region and identifica- 2215 amino acids (Fig. 1A), which can reocilia each [Self et al., 1998]. How- tion of mutations in the myosin-VIIa be expressed in several alternative splice ever, even alleles that show no bundle gene (MYO7A) was presented by Weil forms [Chen et al., 1996, Weil et al., abnormalities and that have adequate et al. [1995] who suggested that 1996; Mburu et al., 1997]. It shares receptor potentials can show abnormal USH1B accounts for about 75% of with other myosins the conserved head cochlear responses and circling behav- USH1 patients. domain, which has the ATP- and actin- ior [Self et al., 1998], suggesting that the The USH1B gene encodes the un- binding domains. Following the head lethality caused by these mutations is conventional myosin-VIIa, a member are five binding sites for regulatory light not in the hair bundle. In the human of the large superfamily of myosin mo- chains such as calmodulin (IQ motifs), myosin-VIIa gene, almost 90 mutations tor proteins that move on cytoplasmic and a short coiled-coil region suggest- have been found that cause hearing loss actin filaments [Weil et al., 1995]. This ing that this myosin normally functions [Weston et al., 1996; Adato et al., 1997; gene was identified through studies of as a dimer. Much of the tail of myosin- Liu et al., 1997a; see summary in Kim- the mouse deafness mutant, shaker-1 VIIa bears two large repeats, each con- berling et al., 1999]. These occur (sh1). Sh1 homozygotes exhibit circling taining a MyTH4 domain and a talin- throughout the gene: 37 of the 48 cod- and hyperactivity, and progressive loss like domain [Chen et al., 1996]. The ing exons bear at least one mutation in of hearing and balance in the first few MyTH4 domain, of about 100 amino different families. Most MYO7A muta- postnatal weeks [Deol, 1956]. Histo- acids, is found in several other members tions cause a typical USH1 phenotype, logical examination of the inner ear of the myosin superfamily, including but some cause DFNB2, a recessive showed progressive degeneration of the myosin-XV, which is also associated deafness without retinal degeneration, hair-cell epithelia of both auditory and with deafness [Probst et al., 1998; Wang and DFNA11, a dominantly inherited et al., 1998]. Certain unusual plant ki- nonsyndromic hearing impairment [Liu nesins also have a MyTH4 domain, et al., 1997b,c; Weil et al., 1997]. In The USH1B gene encodes suggesting that this may be a cargo- another family, affected children have binding domain that can be connected the clinical phenotype of USH3, but the unconventional either to actin-based motors (myosin) have mutations in MYO7A [Liu et al., myosin-VIIa, a member or microtubule-based motors (kinesin). 1998a]. Perhaps not surprisingly, some The talin-like domain of 300 amino ac- mutations seem to impair myosin-VIIa of the large superfamily ids is similar to domains in talin, ezrin, function more than others, and produce of myosin motor proteins moesin and others that are thought to disease of varying extent and severity. It that move on cytoplasmic bind to membrane proteins. Both these is tempting to try to correlate specific domains and the location of myosin- mutations in different domains with actin filaments. VIIa within cells suggest that this myo- specific clinical characteristics, but— sin may be associated with membranes with the exception of these three phe- or vesicles. Finally, there is an SH3 do- notypes that differ from typical vestibular organs, as well as degenera- main between the two repeats, which USH1—it has not yet been possible. tion of the neurons receiving synaptic could be another site for protein- Because of its role in USH1B, input and trophic factors from hair cells protein interaction. myosin-VIIa has received a great deal of [Steel and Bock, 1983]. Because A large number of MYO7A muta- attention in recent years. It is expressed USH1B and sh1 had been mapped to a tions that cause Usher syndrome or re- in the cochlea and retina, as expected, conserved linkage group at human lated hearing disorders have been but also in testis and (to a lesser extent) chromosome band 11q13.5 and mouse found. Eight different alleles have been lung, kidney, intestine and olfactory chromosome 7, respectively, Sh1 and identified in the sh1 mouse, with vary- epithelium [Hasson et al., 1995; Sahly USH1B were hypothesized to be ing degrees of auditory dysfunction. et al., 1997; Wolfrum et al., 1998]. caused by mutations in orthologous These mutations occur throughout the These other organs seem not to be af- REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 161

Figure 1. Domain structure and location of myosin-VIIa. A: Schematic representation of domains. The motor domain binds actin and hydrolyzes ATP. Five IQ domains are thought to bind regulatory light chains. A short predicted coiled-coil region may mediate dimerization. MyTH4 and talin-like domains take up most of rest of the tail, in two large repeats. B: Myosin-VIIa (shaded) occurs in inner (IHC) and outer (OHC) hair cells of the auditory sensory epithelium. C: Highest concentration of m7a in hair cells is found in the pericuticular necklace (pcn) that rings the cuticular plate (cp), and in a band within stereocilia near the ankle links (al).

fected by mutations in MYO7A. In all this region is a set of extracellular fila- endocytosed from the apical surface and of these epithelial tissues, myosin-VIIa ments termed “ankle links,” which may bound for degradation must pass the is associated especially with cilia or mi- serve to hold the stereocilia in register. opposite way. The presence of domains crovilli of the apical surfaces [Wolfrum Perhaps myosin-VIIa is the intracellular in myosin-VIIa similar to those that et al., 1998]. attachment to the cytoskeleton for these cause membrane association in other Within the inner ear, myosin-VIIa extracellular links [Hasson, 1997]. This proteins suggests that myosin-VIIa may is expressed by the sensory hair cells of proposed function may account for the be bound to these vesicles, and may be both auditory and vestibular sensory disorganized hair cell bundles observed part of the transport mechanism [Has- epithelia (Fig. 1B), but not appreciably in most sh1 mice. son, 1997]. The sh1 mouse provides by other cells in the inner ear [Hasson The other concentration is in the further support for membrane traffick- et al., 1995, 1997b; Sahly et al., 1997]. “pericuticular necklace,” a ring near the ing as an important function of myosin- The protein is found throughout the apical surface of the hair cell that is out- VIIa. Whereas wild-type hair cells in cytoplasm of hair cells and the stereo- side the actin-rich cuticular plate but culture normally accumulate aminogly- cilia of the sensory hair bundles, and is inside the circumferential actin band of coside antibiotics from the medium, at highest concentration in two places. the zonula adherens (Fig. 1C). This hair cells from a more severe allele of One (observed primarily in lower ver- zone within the hair cells is distin- the sh1 mouse do not [Richardson et tebrates) is a band within the “ankle” guished by a large number of vesicles, al., 1997]. Other markers indicate that region of the stereocilia at the upper and is thought to be a region of mem- the first stages of the endocytic pathway part of the stereocilia taper. Electron brane trafficking [Kachar et al., 1997]. are intact in severe sh1 hair cells, sug- microscopic localization of myosin- Proteins synthesized in the endoplasmic gesting that myosin-VIIa may function VIIa in this region demonstrates label reticulum that are bound for secretion in a later stage of endocytosis, or might between the actin cores and the mem- or for the stereocilia must be trans- transport an aminoglycoside receptor to branes of stereocilia. Also localized in ported through this zone, and material the membrane. It seems most likely that 162 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) REVIEW a defect in membrane trafficking leads is involved in transport of vesicles or of responsible for all cases of Acadian to the death of hair cells that ultimately membrane-associated proteins at apical Usher syndrome type I [Keats et al., causes deafness. surfaces of cells. In the inner ear, and to 1994]. Thus, for profoundly hearing a lesser extent in the retina, failure of impaired infants of Acadian ancestry, transport leads to the death of the sen- analysis of markers linked to USH1C In the Acadian population, sory cells. may allow differentiation between nonsyndromic hereditary hearing impair- haplotype data are ment and USH1. USH1C consistent with a single Recently, a Lebanese family linked Acadian families in which members had to the USH1C region was reported by mutation being responsible Usher syndrome were described by Saouda et al. [1998]. A nonsyndromic for all cases of Acadian Kloepfer et al. [1966]. The phenotype is hearing impairment locus, DFNB18, Usher syndrome type I. usually USH1, but two Acadian fami- has been mapped to the same region lies with an USH2 phenotype have [Jain et al., 1998]. These families may been described [Smith et al., 1992b]. be helpful in the final identification of The original Acadians were French the USH1C gene. The rd5/rd5 mouse The retinitis pigmentosa that de- fishermen who left the northern coastal mutant has been proposed as a model fines USH in humans results from death regions of France (Brittany, Normandy) for USH1C because the regions of of photoreceptor cells—particularly in the early 1600’s and settled in the mouse chromosome 7 and human rods—in the peripheral retina. In the Canadian territory known as Acadia chromosome 11 to which they map retina, myosin-VIIa is found in two cell (now Nova Scotia and surrounding ar- may share homology [Heckenlively et types: in the photoreceptors them- eas). According to Rushton [1979], al., 1995]. The ERG in these mice has selves, and in the retinal pigmented epi- their population size grew from a few reduced amplitudes that are extin- thelium (RPE) cells, which are in- hundred up to nearly 20,000 by 1755 guished by six months and hearing volved in resynthesizing the when the English ordered their expul- thresholds are above those of controls. chromophore and in phagocytosing sion from Acadia, an event known as spent photoreceptor discs. In the RPE “Le Grand De´rangement des Acadi- cells, myosin-VIIa is specifically in the ens”. The Acadians were dispatched to Eudy et al. [1998] showed microvilli, which face the photorecep- Maryland, the Carolinas, and Georgia tors [Hasson et al., 1995; Liu et al., as well as to French ports and the West that the USH2A gene on 1997d]. In photoreceptors, there is a Indies; over the next 40 years about 1q encodes a novel 1,551 high concentration in the connecting 4,000 Acadians made their way from amino acid protein, which cilium—the narrow stalk connecting these places to Louisiana. At first they inner and outer segments—specifically settled along the banks of the Missis- resembles an estracellular between the microtubules and the sippi River above New Orleans, but matrix protein or a cell membrane [Liu et al., 1997d]. with the Louisiana Purchase in 1803 Sh1 mice do not show retinal de- and statehood in 1812 they were forced adhesion molecule. generation, which is perhaps not sur- west across the Atchafalaya Basin, a 20 prising since the human retinal pathol- mile wide, almost impenetrable swamp. ogy takes years to be apparent. They built their houses on the plains USH1D, USH1E, USH1F Nevertheless, there are subtle defects in among the bayous of southwestern sh1 retinas. For instance, RPE cells of Louisiana and remained relatively iso- The loci USH1D, USH1E, and sh1 mice fail to transport pigment gran- lated because of linguistic, religious, USH1F, were all localized by homozy- ules into the microvilli [Liu et al., and cultural cohesiveness, as well as gosity mapping. Wayne et al. [1996] 1998b]. In sh1 but not wild-type pho- geographic isolation. mapped USH1D to chromosome 10q toreceptor cells, the opsin protein can All of the Acadian USH1 families by analysis of a Pakistani family in be observed in the connecting cilium, show linkage to markers on chromo- which the parents were first cousins. suggesting a failure of transport to the some region 11p15.1 [Smith et al., The nonsyndromic hearing impairment outer segment [Liu et al., 1999b]. A 1992a]. After refinement of the interval locus, DFNB12 [Chaib et al., 1996] has mild defect in transport of outer seg- containing USH1C [Keats et al., 1994; been assigned to the same region. A ment proteins might cause slow accu- Ayyagari et al., 1995], YAC, BAC, and consanguineous Moroccan family pro- mulation with eventual toxicity to pho- PAC contigs were built across the criti- vided the data for assigning USH1E to toreceptors. cal region of approximately 400 kb chromosome 21q21 [Chaib et al., While we still have no definitive [Ayyagari et al., 1996; DeAngelis et al., 1997], and analysis of an inbred Hut- function for myosin-VIIa, and thus no 1998; Higgins et al., 1998]. In the Aca- terite family suggested that USH1F is real understanding of the pathology in dian population, haplotype data are also on chromosome 10 [Wayne et al., USH1B, it seems likely that this protein consistent with a single mutation being 1997], but distinct from USH1D. REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 163

USH2A til Kimberling et al. [1990] and Lewis et towards understanding the functional al. [1990] found linkage to chromo- link between the abnormal or absent USH2A was the first Usher locus some 1 markers in USH2 families but protein and the USH pathology. Al- mapped [Kimberling et al., 1990; Lewis not in USH1 families that genetic het- though myosin-VIIa has been studied et al., 1990]. The chromosome 1q41 erogeneity was demonstrated. Rapid intensely, the precise cascade of events region containing USH2A was nar- progress has been made in advancing that result in USH1 has yet to be rowed to 2.1 cM by Kimberling et al. our understanding of the genetics of the solved. Similar functional studies of the [1995], a YAC contig was constructed Usher syndromes over the past 10 years. protein encoding USH2A are just be- [Sumegi et al., 1996], and the region The initial impetus was the formation ginning, and at least seven other USH was further refined [Bessant et al., 1998; of the Usher Syndrome Consortium, genes remain to be identified. Different Saouda et al., 1998]. After construction which brought together investigators mutations in MYO7A and USH2A of a BAC contig, Eudy et al. [1998] from around the world with an interest lead to a multitude of phenotypes, and identified the USH2A gene by detec- in identifying genes for the Usher syn- expression of hearing and visual impair- tion of mutations in a patient’s DNA. dromes. This was possible because of ments may differ even among those Families unlinked to USH2A suggested the support of NIDCD and the Foun- who are homozygous for the same mu- a second locus, USH2B, which was re- dation Fighting Blindness. tation. These results underscore the cently mapped to chromosome 5q Mapping studies have localized complexity of predicting phenotype [Pieke Dahl et al., 1998]. nine USH genes through linkage to ge- based on genotype and demonstrate the Eudy et al. [1998] showed that the netic markers. As well as delineating the importance of identifying other genetic USH2A gene on 1q encodes a novel region containing the gene, these and environmental factors that modify 1,551 amino acid protein, which re- closely linked markers provide data for the phenotypic expression of the pri- sembles an extracellular matrix protein determining if a relative of an affected mary genetic defect. or a cell adhesion molecule. It contains member is a carrier, and for an endoga- both laminin epidermal growth factor mous population such as the Acadians and fibronectin type II motifs. Similar ACKNOWLEDGMENTS the marker information can be used to proteins are known to influence neural- calculate the probability that any mem- glial interactions and to be involved in This work was supported by the Foun- ber of the population is a carrier. Some synapse development and stabilization. dation Fighting Blindness and the Mar- studies suggest that audiometric and USH2A expression was detected in hu- riott Foundation. electrooculographic analyses may also man fetal cochlea, eye, brain and kid- be helpful for detecting carriers, al- ney, and in adult retina. Three different though results are inconclusive [van REFERENCES mutations were found, with one of Aarem et al., 1995b; Meredith et al., them (2314delG) appearing to be rela- Adato A, Weil D, Kalinski H, Pel-Or Y, Ayadi 1992; Wagenaar et al., 1995, 1996]. 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