Identification Of The Genetic Basis For A Chinese Families Associated With Usher Syndrome

Usher syndrome(USH) is an autosomal recessive disease characterized by theassociation of retinitis pigmentosa(RP), sensorineural hearing loss(SNHL), andsometimes, vestibular dysfunction. Usher syndrome is clinically and geneticallyheterogeneous, and mainly occurs as autosomal recessive inherited forms. To date, twelveloci and nine genes have been found to be responsible for USH, usher type1(USH1) is themost severe form, consisting of profound congenital deafness, vestibular areflexia, andearly onset of progressive RP. MYO7A, which encodes myosin VIIA, has been identifiedas the pathogenic gene for USH1.We investigated a Chinese family with Usher syndrome, A clinical diagnose with thepedigree demonstrate that2individuals were affected (11individuals) and distributed intothree generations. Linkage analysis can’t exclude the result that microsatellite markerD11S937linked with MYO7A. DNA sequence for whole coding region of MYO7Arevealed a missense mutation c.3742G>A in exon29and a splice site mutationc.6051+1G>A, which was found in the donor site of intron44of MYO7A. These twomutations were found to segregate with Usher1in this Chinese family respectively.Subsequent RFLP analysis displayed that both the c.3742G>A and c.6051+1G>A mutationwere not found in any unaffected family members or the100normal controls.The mutation of c.3742G>A lead to p.Glu1248Lys, and c.6051+1G>A may cause aframe shift mutation. The Glutamic acid at position1248(E1248) is highly conservedfrom Homo sapiens to C.elegans according to the alignment of the amino acid sequencesof the first MyTH4domain of MYO7A. The first MyTH4-FERM tandem domainmediates the interaction between MYO7A and the scaffold protein sans (USH1G). TheE1248K mutation may affect this interaction and ruin the normal function of MYO7A.The c.6051+1G>A mutation is a donor splice site mutation in intron44of MYO7A gene.We predicted the impact of the mutation on pre-mRNA splicing of MYO7A using thesoftware, and found that the mutation will destroy the splice site and lead to a truncatedprotein lacking the last~200amino acid residues. The C-terminal tail of the MYO7Acontaining the SH3-MyTH4-FERM domains (1605-2215aa) has been demonstrated tointeract with harmonin (USH1C). The mutant protein may lose the ability to bind harmonin, which acts as a scaffold protein linking the proteins in the cell membrane to theproteins in the cytoskeleton, thus affected the function of MYO7A.Our found expands the mutational spectrum of MYO7A, and there is still a long wayto understand the pathogenesis of Usher syndrome and further overcome the disease.