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Possible Interaction between USH1B and USH3 Gene Products as Implied by Apparent Digenic Deafness Inheritance

1999; Elsevier BV; Volume: 65; Issue: 1 Linguagem: Inglês

10.1086/302438

1537-6605

Avital Adato, Hagar Kalinski, Dominique Weil, Hassan Chaı̈b, Michael Korostishevsky, Batsheva Bonné‐Tamir,

RNA and protein synthesis mechanisms

To the Editor: The Usher syndromes (USHs; MIM 276900–276904, 601067, 60297, and 602083) are a group of autosomal recessive hereditary disorders characterized by the association of sensorineural hearing impairments and progressive visual loss due to retinitis pigmentosa. Three types of USH are distinguished on the basis of severity and onset of auditory and vestibulary dysfunctions. To date, USHs are mapped to nine different genomic loci: USH1A–F, USH2A, USH2B, and USH3 (Hereditary Hearing Loss home page). USH3 (MIM 276902), assigned to chromosome 3q, is regarded as the rarest form of USH (Sankilla et al. Sankilla et al., 1995Sankilla E Pakarinen L Kaariainen H Aitotomaki K Karjalainen S Sistonen P de la Chapelle A Assignment of an Usher syndrome type III (USH3) gene to chromosome 3q.Hum Mol Genet. 1995; 4: 93-98PubMed Google Scholar) The human myosin VIIA gene (MYO7A), located on 11q14, has been shown to be responsible for USH1B (MIM 276903), which is the most common USH1 subtype, accounting for ∼75% of all type 1 cases (Weil et al. Weil et al., 1995Weil D Blanchard S Kaplan J Guilford P Gibson F Walsh J Mburu P et al.Defective myosin VIIA gene responsible for Usher syndrome type 1B.Nature. 1995; 374: 60-61Crossref PubMed Scopus (840) Google Scholar). More recently, MYO7A has also been shown to be responsible for nonsyndromic recessive and dominant deafness (DFNB2 and DFNA11), both types having been assigned to the same 11q chromosomal region (Liu et al. Liu et al., 1997aLiu XZ Walsh J Mburu P Kendrick-Jones J Cope MJTV Steel KP Brown SDM Mutations in the myosin VIIA gene cause non-syndromic recessive deafness.Nat Genet. 1997a; 16: 188-190Crossref PubMed Scopus (363) Google Scholar, Liu et al., 1997bLiu XZ Walsh J Tamagawa Y Kitamura K Nishizawa M Steel KP Brown SDM Autosomal dominant non-syndromic deafness (DFNA11) caused by a mutation in the myosin VIIA gene.Nat Genet. 1997b; 17: 268Crossref PubMed Scopus (256) Google Scholar; Weil et al. Weil et al., 1997Weil D Kussel P Blanchard S Levy G Levi-Acobas F Drira M Ayadi H et al.The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene.Nat Genet. 1997; 16: 191-193Crossref PubMed Scopus (322) Google Scholar). These findings clearly indicate that the enzymatic activity of MYO7A is critical for normal function in the inner ear and that different mutations may cause different dysfunctions that are manifested by distinct phenotypes. Here we report on two novel MYO7A mutations that may have a synergistic effect on the symptoms of another USH different from USH1B. Among USH-affected families recruited as part of a study on the genetics of USH, results of which were published in this journal (Adato et al. Adato et al., 1997Adato A Weil D Kalinski H Pel-Or Y Hammadi A Petit C Korostishevsky M Bonne-Tamir B Mutation profile of all 49 exons of the human myosin VIIA gene and haplotype analysis in Usher 1B families from diverse origins.Am J Hum Genet. 1997; 61: 813-821Abstract Full Text PDF PubMed Scopus (91) Google Scholar), was a nonconsanguineous family of Jewish Yemenite origin that included two affected and six healthy siblings. The two affected brothers in this family have different USH phenotypes. One of the affected brothers (1549 in fig. 1) has a typical USH1 phenotype: he has a history of prelingual profound auditory impairment; he uses sign language for communication, since hearing aids are unhelpful in his case; and developmental milestones (Smith et al. Smith et al., 1994Smith RJH Berlin CI Hejtmancik JF Keats BJB Kimberling WJ Lewis RA Moller CG et al.Clinical diagnosis of the Usher syndromes.Am J Hum Mol. 1994; 50: 32-38Google Scholar) in his childhood are consistent with congenital vestibular dysfunction. The other affected brother (1636 in fig. 1) has a typical USH3 phenotype: he has progressive hearing loss, with postlingual onset; he uses hearing aids and verbal communication; and he receives psychiatric therapy for mental problems. In both affected brothers, the presence of bilateral progressive pigmentary retinopathy has been diagnosed (with onset during early adolescence). Members of this family were typed for 30 polymorphic markers spanning all nine known USH loci (USH1A-F, USH2A, USH2B, and USH3). Marker alleles were identified and arranged into the most likely haplotypes, as shown in figure 1. Haplotype segregation and linkage analysis resulted in exclusion of all USH1 and USH2 loci (LOD scores range from −1.46 to −3.72) and suggested linkage only to the USH3 locus (with a maximum LOD score of 1.35 for marker D3S1279). Both affected brothers showed homozygosity for alleles of four markers: D3S1315, D3S1279, D3S3625, and D3S1294. Homozygosity of USH3 haplotypes in the affected brothers—and the fact that, although not known to be related, both parents originate from a small Jewish community in Yemen—suggest a possible common origin for both USH3-bearing chromosomes. This “USH3 haplotype” was found to be carried (one copy) by only 2 of 54 Jewish Yemenite control subjects tested for its presence. The homozygote interval in both affected brothers and the position of recombination in the paternal chromosome of one healthy progeny (1643; see fig. 1) suggest that the USH3 gene is located between markers D3S1299 and D3S3625. This result is in agreement with the location suggested by Sankilla et al. (Sankilla et al., 1995Sankilla E Pakarinen L Kaariainen H Aitotomaki K Karjalainen S Sistonen P de la Chapelle A Assignment of an Usher syndrome type III (USH3) gene to chromosome 3q.Hum Mol Genet. 1995; 4: 93-98PubMed Google Scholar) and by Joensuu et al. (Joensuu et al., 1996Joensuu T Blanco G Pakarinen L Sistinen P Kaariainen H Brown S de la Chapelle A et al.Refined mapping of Usher syndrome type III locus on chromosome 3, exclusion of candidate genes, and identification of the putative mouse homologous region.Genomics. 1996; 38: 255-263Crossref PubMed Scopus (27) Google Scholar). The order of markers spanning the USH3 linkage region, as presented in figure 1, is cen, D3S2401, D3S1299, D3S1315, D3S1279, D3S3625, D3S1594, tel, in agreement with the order presented in the Whitehead contig (Whitehead Institute for Biomedical Research). However, in this order, the position of the markers D3S1315 and D3S1279, which our findings indicated were the most closely linked to USH3, differs from the one suggested by Joensuu et al. (Joensuu et al., 1996Joensuu T Blanco G Pakarinen L Sistinen P Kaariainen H Brown S de la Chapelle A et al.Refined mapping of Usher syndrome type III locus on chromosome 3, exclusion of candidate genes, and identification of the putative mouse homologous region.Genomics. 1996; 38: 255-263Crossref PubMed Scopus (27) Google Scholar). Since one of the affected brothers had an USH1 phenotype, family members were screened for mutations in the human MYO7A gene, which has been shown to be responsible for USH1B. Two new close nucleotide changes were detected in exon 25 of the gene on one maternal chromosome: a T→C transition and a guanine deletion 5 nt upstream of this transition (fig. 2). None of these changes were found in >200 control chromosomes tested by allele-specific oligonucleotide analysis, as described by Whithney et al. (Whithney et al., 1993Whithney MA Saito H Jakobs PM Gibson RA Moss RE Grompe M A common mutation in the FACC gene causes Fancini anemia in Ashkenazi Jews.Nat Genet. 1993; 4: 202-205Crossref PubMed Scopus (122) Google Scholar). This mutated MYO7A is carried by the brother with the USH1 phenotype (1549) but not by his affected brother with the USH3 phenotype (1636). The mother (1637) and two unaffected siblings (1638 and 1639), who are all double heterozygotes for the mutated MYO7A and for a single USH3 haplotype, show no evidence of any USH symptoms or nonsyndromic deafness. This suggests a digenic inheritance pattern, with a possible synergistic interaction between MYO7A and the USH3 gene product, where presence of a single defective MYO7A allele seems to increase the severity of deafness as a part of the clinical symptoms associated with USH3. Evidence for digenic inheritance of nonsyndromic deafness was already presented in the case of a Swedish family (Balciuniene et al. Balciuniene et al., 1998Balciuniene J Dahl N Borg E Samuelsson E Koisti MJ Pettersson U Jazin EE Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family.Am J Hum Genet. 1998; 63: 786-793Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), whose affected members were carriers of DFNA2 and/or DFNA12. Increased severity of deafness was found in family members that were carriers of both alleles. This clear additive effect differs from the situation in our Yemenite family, where mutated MYO7A appears to be phenotypically expressed only on the background of two defective USH3 alleles, suggesting an interaction between the MYO7A and the USH3 gene products. Digenic inheritance was also suggested as one of the possible explanations in the case of DFNB15 (Chen et al. Chen et al., 1997Chen A Wayne S Bell A Ramesh A Srisailapathy CR Sccott DA Sheffield VC et al.New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p.Am J Med Genet. 1997; 71: 467-471Crossref PubMed Scopus (36) Google Scholar). This is an autosomal recessive nonsyndromic deafness, found in a family of Indian origin, linked to two loci on chromosomes 3q and 19p. Most interestingly in relation to our work, one of these loci, 3q21.3-3q25.2, includes the USH3 locus and the other, 19p13.3p13.1, includes (among others) the MYO1F gene (Hasson et al. Hasson et al., 1996Hasson T Skowron JF Gilbert DJ Avraham KB Perry WL Bement WM Anderson BL et al.Mapping of unconventional myosins in mouse and humans.Genomics. 1996; 36: 431-439Crossref PubMed Scopus (67) Google Scholar), which is another member of the unconventional myosin group. Human MYO7A is a member of the unconventional myosins group (Weil et al. Weil et al., 1996Weil D Levy G Shahly I Levi-Acobas F Blanchard S El-Amraou A Crozet F et al.Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia.Proc Natl Acad Sci USA. 1996; 93: 3232-3237Crossref PubMed Scopus (146) Google Scholar). All myosins have three different functional domains defined within their heavy chains: an N-terminal motor domain, a regulatory (light-chain–binding) domain, and a tail domain that varies dramatically in length and in sequence among myosins (Mooseker and Cheney Mooseker and Cheney, 1995Mooseker MS Cheney RE Unconventional myosins.Annu Rev Cell Dev Biol. 1995; 11: 633-675Crossref PubMed Scopus (379) Google Scholar). The functions of myosin-tail domains are largely unknown. However, a common assumption is that the tail directs the interaction of a given myosin with its cargo (Mermall et al. Mermall et al., 1998Mermall V Post PL Mooseker MS Unconventional myosins in cell movement, membrane traffic, and signal transduction.Science. 1998; 279: 527-533Crossref PubMed Scopus (510) Google Scholar). MYO7A is predicted to dimerize, on the basis of the coiled-coil sequence motif at the start of its tail region. The sequence changes detected in exon 25 of MYO7A in some members of the presented family are expected to result, at the protein level, in a Leu→Pro substitution at codon 1087 and in a frameshift of the reading frame starting at codon 1089. Both these AA codons are located after the coiled-coil domain of the protein. This frameshift would result in the formation of a UGA stop codon 18 amino acids downstream from the deletion site and, therefore, in the translation of a truncated protein that lacks >50% of its normal AA sequence, which comprises most of the MYO7A tail domain. Segregation of the mutated MYO7A with healthy members of this family and, on the other hand, with the more severe USH phenotype, suggests a possible biological interaction between MYO7A and the USH3 gene products. This mutated MYO7A appears to be phenotypically expressed only on the background of two USH3 alleles. Many disease mutations that introduce stop codons were found to lead to mRNA destabilization, as in the mouse MYO6 sv allele (Avraham et al. Avraham et al., 1995Avraham KB Hasson T Steel KP Kingsley DM Russell LB Mooseker MS Copeland NG et al.The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner hair cells.Nat Genet. 1995; 11: 369-374Crossref PubMed Scopus (402) Google Scholar). In such a case, segregation of the mutated MYO7A, as described above, could indicate that the normal USH3 gene product may affect the stabilization of the MYO7A mRNA or the protein. If the mutated MYO7A in this Yemenite family was translated, then it would not lack its coiled-coil sequence motif. Unlike the case of DFNB11, where a 9 bp deletion in the coiled-coil region of MYO7A was suggested to have a dominant negative effect (Liu et al. Liu et al., 1997bLiu XZ Walsh J Tamagawa Y Kitamura K Nishizawa M Steel KP Brown SDM Autosomal dominant non-syndromic deafness (DFNA11) caused by a mutation in the myosin VIIA gene.Nat Genet. 1997b; 17: 268Crossref PubMed Scopus (256) Google Scholar), segregation of the mutated MYO7A with healthy members of our family clearly determines the recessive nature of its mutation. There are several possible explanations for this difference. The truncated MYO7A produced in our case may be incompetent for dimerization, since it is unknown whether the remainder of the tail is required for self assembly or if the truncated molecule may be destabilized. Another possible reason is the formation of a partially functional heterodimer. These possibilities would yield ≤50% of the normal protein amounts. In any kind of direct or indirect USH3-MYO7A protein interaction, a reduced-dosage effect of active MYO7A protein is likely to have a synergistic effect on the background of the two impaired alleles of the USH3 gene product. One possible explanation for the USH3-MYO7A interaction is that the USH3 protein might be involved in targeting or binding MYO7A to the plasma membrane. The tail of MYO7A consists of a direct repeat containing two elements. The distal element, the talinlike domain, shows significant homology to the N-terminus of talin and limited homology to the N-termini of other members of the band-4.1 superfamily of actin-binding proteins (Weil et al. Weil et al., 1996Weil D Levy G Shahly I Levi-Acobas F Blanchard S El-Amraou A Crozet F et al.Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia.Proc Natl Acad Sci USA. 1996; 93: 3232-3237Crossref PubMed Scopus (146) Google Scholar; Chen et al. Chen et al., 1997Chen A Wayne S Bell A Ramesh A Srisailapathy CR Sccott DA Sheffield VC et al.New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p.Am J Med Genet. 1997; 71: 467-471Crossref PubMed Scopus (36) Google Scholar). In talin and in band 4.1, this region binds to acidic phospholipids and mediates protein-protein interactions. Therefore, it is thought that talinlike motifs serve to bind and/or target the myosin to the plasma membrane (Cheney et al. Cheney et al., 1993Cheney R Riley MA Mooseker MS Phylogenetic analysis of the myosin super family.Cell Motil Cytoskeleton. 1993; 24: 215-223Crossref PubMed Scopus (233) Google Scholar; Titus et al. Titus, 1997Titus MA Unconventional myosins: new frontiers in actin-based motors.Trends Cell Biol. 1997; 7: 119-123Abstract Full Text PDF PubMed Scopus (51) Google Scholar). It is also possible that USH3 is a cytoskeletal component and as such interacts with the MYO7A protein: Actin cytoskeleton is essential for proper the function of the inner ear, and deafness-associated genes such as MYO7A and MYO15 as well as the human diaphanous protein are assumed to be cytoskeletal components (Vasiliki and Petit Vasiliki and Petit, 1998Vasiliki K Petit C The fundamental and medical impacts of recent progress in research on hereditary hearing loss.Hum Mol Genet. 1998; 7: 1589-1597Crossref PubMed Scopus (76) Google Scholar). The MYO7A protein may also serve an inner hair-cell–specific role distinct from its role in actin. This role might be complementary to the function of the USH3 gene product. For example, in mice, MYO7A was found to be involved in hair-cell vesicle trafficking of aminoglycosides, which are known to induce ototoxicity (Richardson et al. Richardson et al., 1997Richardson GP Froge A Kros CJ Fleming J Brown SD Steel KP Myosin VIIA is required for aminoglycoside accumulation in cochlear hair cells.J Neurosci. 1997; 17: 9506-9519Crossref PubMed Google Scholar). We would like to express our gratitude to Elias Kavakov and his staff members at the Center for Deaf-Blind Persons-Beth David Institute in Tel Aviv. We thank all family members who participated in this study. We also thank Tama Hasson for critical comments on our manuscript. This work was supported in part by an Israel Science Foundation research grant (1140041), a Ministry of Health grant (1140091), and an Applebaum Foundation grant (1140111) (to B.B.T.); and a European Economic Community grant (PL951324; to C.P.). This work was done as part of A. A.'s Ph.D. project.