RESUMO
Ezrin, radixin, and moesin are paralogous proteins that make up the ERM family and function as cross-linkers between integral membrane proteins and actin filaments of the cytoskeleton. In the mouse, a null allele of Rdx encoding radixin is associated with hearing loss as a result of the degeneration of inner ear hair cells as well as with hyperbilirubinemia due to hepatocyte dysfunction. Two mutant alleles of RDX [c.1732G>A (p.D578N) and c.1404_1405insG (p.A469fsX487)] segregating in two consanguineous Pakistani families are associated with neurosensory hearing loss. Both of these mutant alleles are predicted to affect the actin-binding motif of radixin. Sequence analysis of RDX in the DNA samples from the original DFNB24 family revealed a c.463C>T transition substitution that is predicted to truncate the protein in the FERM domain (F for 4.1, E for ezrin, R for radixin, and M for moesin) (p.Q155X). We also report a more complete gene and protein structure of RDX, including four additional exons and five new isoforms of RDX that are expressed in human retina and inner ear. Further, high-resolution confocal microscopy in mouse inner ear demonstrates that radixin is expressed along the length of stereocilia of hair cells from both the organ of Corti and the vestibular system.
Assuntos
Proteínas do Citoesqueleto/genética , Perda Auditiva/genética , Proteínas de Membrana/genética , Mutação , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 11 , Clonagem Molecular , Proteínas do Citoesqueleto/metabolismo , Primers do DNA , Orelha Interna/metabolismo , Éxons , Ligação Genética , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Dados de Sequência Molecular , Paquistão , Linhagem , Retina/metabolismo , Homologia de Sequência de AminoácidosRESUMO
We have identified five different homozygous recessive mutations in a novel gene, TMIE (transmembrane inner ear expressed gene), in affected members of consanguineous families segregating severe-to-profound prelingual deafness, consistent with linkage to DFNB6. The mutations include an insertion, a deletion, and three missense mutations, and they indicate that loss of function of TMIE causes hearing loss in humans. TMIE encodes a protein with 156 amino acids and exhibits no significant nucleotide or deduced amino acid sequence similarity to any other gene.