title: Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing.
abstract: Usher syndrome (USH) is an autosomal recessive condition characterized by sensorineural hearing loss, vestibular dysfunction, and visual impairment due to retinitis pigmentosa. Truncating mutations in the cadherin-23 gene (CDH23) result in Usher syndrome type 1D (USH1D), whereas missense mutations affecting strongly conserved motifs of the CDH23 protein cause non-syndromic deafness (DFNB12). Four missense mutations constitute an exception from this genotype-phenotype correlation: they have been described in USH1 patients in homozygous state. Using a minigene assay, we have investigated these changes (c.1450G>C, p.A484P; c.3625A>G, p.T1209A; c.4520G>A, p.R1507Q; and c.5237G>A, p.R1746Q) for a possible impact on mRNA splicing which could explain the syndromic phenotype. While in silico analysis suggested impairment of splicing in all four cases, we found aberrant splicing for only one mutation, p.R1746Q. However, splicing was normal in case of p.A484P, p.T1209A and p.R1507Q. These three latter CDH23 missense mutations could interfere with functions of both, the auditory and the visual system. Alternatively, they could represent rare non-pathogenic polymorphisms.
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Elvir
authors.initials: E
authors.lastname: Becirovic
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.forename: Ditta
authors.initials: D
authors.lastname: Nagy
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Mathias Wolfgang
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Hanno Jörn
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D052245:Usher Syndromes / Q000145:classification / Q000235:genetics* / Q000378:metabolism
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D017931:DNA Primers; D018076:DNA, Complementary; D012333:RNA, Messenger