PMC

Segregation of the mutations in MYO7A, USH1G and USH2A in family U3. Arrow indicates the deaf proband.

Genetic evidence for presumably pathogenic mutations in more than one USH gene in six families. The index case in family U24 is indicated by an arrow.

Interspecies conservation of amino acid residues mutated in patients carrying presumably pathogenic mutations in several USH genes. Representative stretches of amino acid sequences from each of the USH proteins from various species were aligned, and identical residues highlighted with shading. Residues involved in missense mutations are underlined. Protein ID accession numbers are indicated in parentheses. Orthologs of MYO7A, USH2A and WHRN are present in the cnidarian Ciona savignyi; they encode proteins that have 53.5%, 36.5%, and 24.7% (whirlin short isoform) of sequence identity with the human proteins, respectively. Notably, the P1220 residue of myosin VIIa, and the G1301 and C3307 residues of usherin, which are involved in the USH patients' missense mutations, are conserved in C. savignyi. Incidentally, all the new USH2A missense mutations detected in our series of patients affect residues that are also conserved in this species.

Schematic representation of USH1 and USH2 proteins and localization of the novel, presumably pathogenic mutations. The long isoform of each USH protein is shown. *Splice site mutations. Abbreviations: IQ motifs, isoleucine-glutamine motifs; SAH, stable single α-helix; MyTH4, myosin tail homology 4; FERM, band 4.1-ezrin-radixin-moesin; PDZ, PSD95, discs large, ZO-1; PST, proline-serine-threonine-rich region; EC, extracellular cadherin; TM, transmembrane domain; Ank, ankyrin domains; cent, central region; SAM, sterile alpha motif; LamG, laminin G; LamG/TspN/PTX, N-terminal thrombospondin/pentaxin/laminin G-like domain; LamNT, laminin N-terminal; EGF Lam, laminin-type EGF-like; FnIII, fibronectin type III; VLGR1, very large G protein-coupled receptor 1; Calx, Ca²⁺-binding calcium exchanger β; EAR, Epilepsy Associated Repeats; Ala/Gly/Ser rich, alanine, glycine, and serine rich region; Pro rich, proline rich region.