Portal de Periódicos da CAPES

USH1A: Chronicle of a Slow Death

2006; Elsevier BV; Volume: 78; Issue: 2 Linguagem: Inglês

10.1086/500275

1537-6605

S. Gerber, Dominique Bonneau, Brigitte Gilbert, Arnold Münnich, Jean‐Louis Dufier, Jean‐Michel Rozet, Josseline Kaplan,

RNA and protein synthesis mechanisms

To the Editor: Usher syndrome type I (USH1) is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually within the 1st decade), and constant vestibular dysfunction (Fishman et al. Fishman et al., 1983Fishman GA Kumar A Joseph ME Torok N Aderson RJ Usher's syndrome: ophthalmic and neuro-otologic findings suggesting genetic heterogeneity.Arch Ophthalmol. 1983; 101: 1367-1374Crossref PubMed Scopus (106) Google Scholar). USH1 is genetically heterogeneous, since seven different loci have been mapped to human chromosomes, five of which are identified: USH1A on 14q32.1 (MIM 276900), USH1B on 11q13.5 (myosin VIIA [MIM 276903]), USH1C on 11p15.1 (harmonin [MIM 276904]), USH1D on 10q21–q22 (cadherin 23 [MIM 601067]), USH1E on 21q21 (MIM 602097), USH1F on 10q21–22 (protocadherin 15 [MIM 602083]), and USH1G on 17q24–q25 (SANS [MIM 606943]). The USH1A locus was described in 1992 in nine families originating from the same small area of the Poitou-Charentes region, around the town of Bressuire in France (Kaplan et al. Kaplan et al., 1992Kaplan J Gerber S Bonneau D Rozet JM Delrieu O Briard ML Dollfus H Ghazi I Dufier JL Frézal J Munnich A A gene for Usher syndrome type I (USH1A) maps to chromosome 14q.Genomics. 1992; 14: 979-987Crossref PubMed Scopus (131) Google Scholar; Larget-Piet et al. Larget-Piet et al., 1994Larget-Piet D Gerber S Bonneau D Rozet JM Marc S Ghazi I Dufier JL David A Bitoun P Weissenbach J Genetic heterogeneity of Usher syndrome type 1 in French families.Genomics. 1994; 21: 138-143Crossref PubMed Scopus (41) Google Scholar). The symbol "USH1A" and the additional trivial designation of "French variety" was assigned to that form of Usher syndrome. In 1995, mutations of the unconventional myosin VIIA (GenBank accession number NM_000260) were found to account for the USH1B locus (Kimberling et al. Kimberling et al., 1992Kimberling WJ Moller CG Davenport S Priluck IA Beighton PH Greenberg J Reardon W Weston MD Kenyon JB Grunkemeyer JA Pieke Dahl S Overbeck LD Blackwood DJ Brower AM Hoover DM Rowland P Smith RJH Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11.Genomics. 1992; 14: 988-994Crossref PubMed Scopus (129) Google Scholar; Weil et al. Weil et al., 1995Weil D Blanchard S Kaplan J Guilford P Gibson F Walsh J Mburu P Valera A Levilliers J Weston MD Kelley PM Kimberling WJ Wagenaar M Levi-Acobas F Larget-Piet D Munnich A Steel KP Brown SDM Petit C Defective myosin VIIA gene responsible for Usher syndrome type 1B.Nature. 1995; 374: 60-61Crossref PubMed Scopus (837) Google Scholar). Myosin VIIA is believed to play a role in the transport of membrane-associated proteins at apical surfaces of cells and, in the inner ear, it may be essential for adhesion between stereocilia (Keats and Savas Keats and Savas, 2004Keats BJB Savas S Genetic heterogeneity in Usher syndrome.Am J Med Genet A. 2004; 130: 13-16Crossref Scopus (39) Google Scholar). Candidate genes at the USH1A locus were selected with regard to these functional data. Four attractive candidate genes were studied in turn: (1) the gene encoding cyclin K (CCNK, also known as CPR4 [GenBank accession numbers AF270825–AF270832]), whose expression in mouse overlaps with myosin VIIA (Edwards et al. Edwards et al., 1997Edwards MC Liegeois N Horecka J DePinho RA Sprague Jr, GF Tyers M Elledge SJ Human CPR (cell cycle progression restoration) genes impart a Far-phenotype on yeast cells.Genetics. 1997; 147: 1063-1076Crossref PubMed Google Scholar); (2) the gene encoding human echinoderm microtubule-associated protein-like (HuEMAP [GenBank accession number AJ420603]), a protein that may modify the dynamics of microtubules and that had long been regarded as a "strong candidate for the Usher syndrome type IA gene" (Eudy et al. Eudy et al., 1997Eudy JD Ma-Edmonds M Yao SF Talmadge CB Kelley PM Weston MD Kimberling WJ Sumegi J Isolation of a novel human homologue of the gene coding for echinoderm microtubule-associated protein (EMAP) from the Usher syndrome type 1a locus at 14q32.Genomics. 1997; 43: 104-106Crossref PubMed Scopus (34) Google Scholar); (3) the gene encoding the Kinesin-light chain 2 (KNS2 [GenBank accession numbers AF267517–AF267531]), which belongs to a class of microtubule-associated motor proteins (Cabeza-Arvelaiz et al. Cabeza-Arvelaiz et al., 1993Cabeza-Arvelaiz Y Shih LC Hardman N Asselbergs F Bilbe G Schmitz A White B Siciliano MJ Lachman LB Cloning and genetic characterization of the human kinesin light-chain (KLC) gene.DNA Cell Biol. 1993; 12: 881-892Crossref PubMed Scopus (27) Google Scholar); and, finally, (4) the gene encoding the human jagged 2 (JAG2) protein, a ligand which activates the Notch and related receptors and was suggested to play a role in the regulation of hair development in the inner ear (Oda et al. Oda et al., 1997Oda T Elkahloun AG Meltzer PS Chandrasekharappa SC Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the alagille syndrome critical region at 20p12.Genomics. 1997; 43: 376-379Crossref PubMed Scopus (55) Google Scholar; Lanford et al. Lanford et al., 1999Lanford PJ Lan Y Jiang R Lindsell C Weinmaster G Gridley T Kelley MW Notch signalling pathway mediates hair cell development in mammalian cochlea.Nat Genet. 1999; 21: 289-292Crossref PubMed Scopus (373) Google Scholar; Deng et al. Deng et al., 2000Deng Y Madan A Banta AB Friedman C Trask BJ Hood L Li L Characterization, chromosomal localization, and the complete 30-kb DNA sequence of the human Jagged2 (JAG2) gene.Genomics. 2000; 63: 133-138Crossref PubMed Scopus (14) Google Scholar). As for HuEMAP, the JAG2 gene had also long been regarded as a strong candidate for USH1A. All these genes were sequenced in one patient of each of the nine USH1A families originating from the Bressuire region, but no disease-associated alteration has been identified in any of them. Later, we had the opportunity to study an additional multiplex family affected with Usher syndrome type I originating from the Bressuire region. Surprisingly, in this family, linkage of the disease gene to the USH1A locus was clearly excluded, but it was compatible with the USH1B locus. Furthermore, we had the opportunity to study a last-born, healthy individual belonging to one of the eight original USH1A families of Bressuire reported in 1992 (individual II6, family 1) (Kaplan et al. Kaplan et al., 1992Kaplan J Gerber S Bonneau D Rozet JM Delrieu O Briard ML Dollfus H Ghazi I Dufier JL Frézal J Munnich A A gene for Usher syndrome type I (USH1A) maps to chromosome 14q.Genomics. 1992; 14: 979-987Crossref PubMed Scopus (131) Google Scholar). Surprisingly, this healthy individual, who was unavailable in 1992, turned out to be haploidentical to his two affected sibs, which strongly challenges for the first time the existence of the USH1A locus. At that time, these two unexpected data prompted us to screen for mutations in the major USH1 gene, the myosin VIIA in USH1A families. The results of this study signed the death warrant of the USH1A locus, since mutations were identified in six of these nine original families hailing from the Bressuire region (table 1).Table 1Myosin VIIA Mutations Identified in Seven USH1 Families Originating from BressuireAllele 1Allele 2FamilyExonNucleotide ChangePredicted ChangeExonNucleotide ChangePredicted Change248c.6557T→Cp.Leu2186ProaOriginal mutation absent from 100 control individuals (200 chromosomes).43c.5884-5887delTTCTp.Phe1962fsX19684.II321c.2513G→Ap.Trp838X9c.938delCp.Thr313fsX3614.II49c.999T→Gp.Tyr333X29c.3719G→Ap.Arg1240GlnbJanecke et al. 1999.4.II529c.3719G→Ap.Arg1240GlnbJanecke et al. 1999.9c.999T→Gp.Tyr333X4.III121c.2513G→Ap.Trp838X9c.999T→Gp.Tyr333X544c.6025delGp.Ala2009fsX204044c.6025delGp.Ala2009fsX204068c.755A→Gp.Tyr252CysaOriginal mutation absent from 100 control individuals (200 chromosomes).37c.5101C→Tp.Arg1701X731c.4012delCp.Arg1338fsX139843c.5884-5887delTTCTp.Phe1962fsX196896c.494C→Tp.Thr165McOuyang et al. 2005.6c.494C→Tp.Thr165McOuyang et al. 2005.Novel Family44c.6025delGp.Ala2009X20409c.999T→Gp.Tyr333XNote.—The A of the start codon (ATG) of the GenBank cDNA sequence is nucleotide +1 for the myosin VIIA gene. The numbers of families and of individuals of family 4, which consists of four nuclear subfamilies, refer to Larget-Piet et al. (Larget-Piet et al., 1994Larget-Piet D Gerber S Bonneau D Rozet JM Marc S Ghazi I Dufier JL David A Bitoun P Weissenbach J Genetic heterogeneity of Usher syndrome type 1 in French families.Genomics. 1994; 21: 138-143Crossref PubMed Scopus (41) Google Scholar).a Original mutation absent from 100 control individuals (200 chromosomes).b Janecke et al. Janecke et al., 1999Janecke AR Meins M Sadeghi M Grundmann K Apfelstedt-Sylla E Zrenner E Rosenberg T Gal A Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity.Hum Mutat. 1999; 13: 133-140Crossref PubMed Scopus (57) Google Scholar.c Ouyang et al. Ouyang et al., 2005Ouyang XM Yan D Du LL Hejtmancik JF Jacobson SG Nance WE Li AR Angeli S Kaiser M Newton V Brown SD Balkany T Liu XZ Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population.Hum Genet. 2005; 116: 292-299Crossref PubMed Scopus (88) Google Scholar. Open table in a new tab Note.— The A of the start codon (ATG) of the GenBank cDNA sequence is nucleotide +1 for the myosin VIIA gene. The numbers of families and of individuals of family 4, which consists of four nuclear subfamilies, refer to Larget-Piet et al. (Larget-Piet et al., 1994Larget-Piet D Gerber S Bonneau D Rozet JM Marc S Ghazi I Dufier JL David A Bitoun P Weissenbach J Genetic heterogeneity of Usher syndrome type 1 in French families.Genomics. 1994; 21: 138-143Crossref PubMed Scopus (41) Google Scholar). In summary, among the 10 families originating from the Bressuire region (9 reported by Larget-Piet et al. [Larget-Piet et al., 1994Larget-Piet D Gerber S Bonneau D Rozet JM Marc S Ghazi I Dufier JL David A Bitoun P Weissenbach J Genetic heterogeneity of Usher syndrome type 1 in French families.Genomics. 1994; 21: 138-143Crossref PubMed Scopus (41) Google Scholar] and 1 additional family reported in this letter), 7 harbored mutations in the myosin VIIA gene, 1 was compatible with linkage to the USH1D and USH1E loci, and 1 excluded all USH1 loci (including the 14q32.1 region). With regard to the last family, no DNA was available for further linkage studies at all USH1 loci. What lessons can one draw from this disappointing history? First of all, we should not have made the hypothesis of a founder effect without evidence for linkage disequilibrium. Consequently, the Morton test used in the original study (Kaplan et al. Kaplan et al., 1992Kaplan J Gerber S Bonneau D Rozet JM Delrieu O Briard ML Dollfus H Ghazi I Dufier JL Frézal J Munnich A A gene for Usher syndrome type I (USH1A) maps to chromosome 14q.Genomics. 1992; 14: 979-987Crossref PubMed Scopus (131) Google Scholar) may not always be applicable when the geographic origin is the only criterion for the subdivision of families. Second, we fell in love with the hypothesis of a "French variety" of USH1 because, in the middle of the 19th century, the first Institution for Deaf and Blind Children was created in the Poitou-Charentes region to receive 16 unrelated deaf and blind children. It is probable that some of them were affected with Usher syndrome. With consideration of the lack of intermixing of populations at this time, it is conceivable that one USH1 mutation settled in the region. Besides, after the mapping of the USH1A locus on chromosome 14q32.1, many very attractive candidate genes lying within the genetic interval were offered to our group for mutational screening in patients. To date, in light of our recent genetic studies showing that most patients of Bressuire harbor different myosin VIIA mutations, it is likely that, when the Institution for Deaf and Blind Children opened, several USH1 families moved to the Poitou-Charentes region and that several of these mutations were transmitted through generations. This was also the case in the Newfoundland population from an isolated region of Canada where a high incidence of Bardet-Biedl syndrome (BBS) exists. The genetic study of 17 BBS kindreds hailing from this region showed that at least four loci might account for the disease (Woods et al. Woods et al., 1999Woods MO Young TL Parfrey PS Hefferton D Green JS Davidson WS Genetic heterogeneity of Bardet-Biedl syndrome in a distinct Canadian population: evidence for a fifth locus.Genomics. 1999; 55: 2-9Crossref PubMed Scopus (54) Google Scholar). In conclusion, it is now clear that (1) the USH1A locus does not exist; (2) the myosin VIIA gene is the major USH1 gene, and, finally, (3) in our series, all USH1 loci were excluded in one USH1A family, suggesting that at least one additional gene should be identified. We are very grateful to all families who agreed to send new blood samples. We thank Dominique Weil for providing us with the myosin VIIA primers. This work was supported by the Association Retina France.