Publications (7)22.66 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: We report on the isolation and initial characterization of a human alpha-tubulin gene named TUBA2. This gene is located in the 13q11 region and has been considered a candidate gene for two nonsyndromic deafnesses, DFNB1 and DFNA3. The gene, with a minimum size of 6.5 kb, contains five exons and four introns starting at codon positions 1, 76, 125, and 352, one of which is inserted between the initiation methionine codon and the codon specifying the second amino acid, arginine 2. Neither rearrangement nor point mutation was found in the coding region of the gene in DFNB1- and DFNA3-affected patients. The gene was therefore unlikely to be responsible for either of these deafnesses. During the characterization of TUBA2, the gene encoding connexin 26 was proven to be responsible for both DFNB1 and DFNA3 (D. P. Kelsell et al., 1997, Nature 387: 80-83). However, the present data offer the possibility of testing the involvement of the TUBA2 gene in the Clouston hidrotic ectodermal dysplasia and the Kabuki syndrome, two genetic diseases that have recently been mapped to the 13q11 region.
- [Show abstract] [Hide abstract] ABSTRACT: Several lines of evidence indicate a crucial role for unconventional myosins in the function of the sensory hair cells of the inner ear. We report here the characterization of the cDNAs encoding two unconventional type I myosins from a mouse cochlear cDNA library. The first cDNA encodes a putative protein named Myo1c, which is likely to be the murine orthologue of the bullfrog myosin I beta and which may be involved in the gating of the mechanotransduction channel of the sensory hair cells. This myosin belongs to the group of short-tailed myosins I, with its tail ending shortly after a polybasic, TH-1-like domain. The second cDNA encodes a novel type I myosin Myo1f which displays three regions: a head domain with the conserved ATP- and actin-binding sites, a neck domain with a single IQ motif, and a tail domain with the tripartite structure initially described in protozoan myosins I. The tail of Myo1f includes (1) a TH-1 region rich in basic residues, which may interact with anionic membrane phospholipids; (2) a TH-2 proline-rich region, expected to contain an ATP-insensitive actin-binding site; and (3) a SH-3 domain found in a variety of cytoskeletal and signaling proteins. Northern blot analysis indicated that the genes encoding Myo1c and Myo1f display a widespread tissue expression in the adult mouse. Myo1c and Myo1f were mapped by in situ hybridization to the chromosomal regions 11D-11E and 17B-17C, respectively. The human orthologuous genes MYO1C and MYO1F were also characterized, and mapped to the human chromosomal regions 17p18 and 19p13.2-19p13.3, respectively.
- [Show abstract] [Hide abstract] ABSTRACT: The gene encoding human myosin VIIA is responsible for Usher syndrome type III (USH1B), a disease which associates profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. The reconstituted cDNA sequence presented here predicts a 2215 amino acid protein with a typical unconventional myosin structure. This protein is expected to dimerize into a two-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily. The gene consists of 48 coding exons. It encodes several alternatively spliced forms. In situ hybridization analysis in human embryos demonstrates that the myosin VIIA gene is expressed in the pigment epithelium and the photoreceptor cells of the retina, thus indicating that both cell types may be involved in the USH1B retinal degenerative process. In addition, the gene is expressed in the human embryonic cochlear and vestibular neuroepithelia. We suggest that deafness and vestibular dysfunction in USH1B patients result from a defect in the morphogenesis of the inner ear sensory cell stereocilia.
- [Show abstract] [Hide abstract] ABSTRACT: Two forms of inherited childhood nonsyndromic deafness (DFNB1 and DFNA3) and a Duchenne-like form of progressive muscular dystrophy (LGMD2C) have been mapped to the pericentromeric region of chromosome 13. To clone the genes responsible for these diseases we constructed a yeast artificial chromosome (YAC) contig spanning an 8-cM region between the polymorphic markers D13S175 and D13S221. The contig comprises 24 sequence-tagged sites, among which 15 were newly obtained. This contig allowed us to order the polymorphic markers centromere-D13S175-D13S141-D13S143-D13S115-AFM128yc1-D13S292-D13S283-AFM323vh5-D13S221-telomere. Eight expressed sequence tags, previously assigned to 13q11-q12 (D13S182E, D13S183E, D13S502E, D13S504E, D13S505E, D13S837E, TUBA2, ATP1AL1), were localized on the YAC contig. YAC screening of a cDNA library derived from mouse cochlea allowed us to identify an α-tubulin gene (TUBA2) that was subsequently precisely mapped within the candidate region.
- [Show abstract] [Hide abstract] ABSTRACT: Le syndrome de Usher associe une surdité congénitale et une rétinite pigmentaire évolutive. Il comprend trois formes cliniques qui se transmettent toutes selon le mode autosomique récessif. Le type I désigne la forme la plus grave; au moins quatre genes distincts en sont responsables. Nous avons récemment identifié le gene responsable du type IB. Ce gene code pour une myosine non conventionnelle, la myosine VIIA.