Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing

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. © 2008 Wiley‐Liss, Inc.

[1]  J. Hampe,et al.  Single base‐pair substitutions in exon–intron junctions of human genes: nature, distribution, and consequences for mRNA splicing , 2007, Human mutation.

[2]  M. Claustres,et al.  Large genomic rearrangements within the PCDH15 gene are a significant cause of USH1F syndrome , 2007, Molecular vision.

[3]  C. Möller,et al.  Longterm visual prognosis in Usher syndrome types 1 and 2. , 2006, Acta ophthalmologica Scandinavica.

[4]  A. Vielle,et al.  Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90% , 2006, Journal of Medical Genetics.

[5]  A. Munnich,et al.  USH1A: chronicle of a slow death. , 2006, American journal of human genetics.

[6]  B. Bembi,et al.  Characterization of two novel GBA mutations causing Gaucher disease that lead to aberrant RNA species by using functional splicing assays , 2006, Human mutation.

[7]  Steve D. M. Brown,et al.  Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population , 2005, Human Genetics.

[8]  C. Cremers,et al.  Variable Clinical Features in Patients with CDH23 Mutations (USH1D-DFNB12) , 2004, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[9]  M. Marmor,et al.  Standard for clinical electroretinography (2004 update) , 2004, Documenta Ophthalmologica.

[10]  P. Sieving,et al.  PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. , 2003, Human molecular genetics.

[11]  C. Petit,et al.  Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. , 2003, Human molecular genetics.

[12]  J. W. Askew,et al.  CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. , 2002, American journal of human genetics.

[13]  A. Pandya,et al.  Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness , 2002, Human Genetics.

[14]  S. Riazuddin,et al.  Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC , 2002, Human Genetics.

[15]  B. Lorenz,et al.  Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D , 2002, Human mutation.

[16]  Bo Yuan,et al.  Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. , 2001, American journal of human genetics.

[17]  S. Schwartz,et al.  Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. , 2001, Human molecular genetics.

[18]  Sue Malcolm,et al.  A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene , 2000, Nature Genetics.

[19]  A. Mansour,et al.  A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C , 2000, Nature Genetics.

[20]  Steve D. M. Brown,et al.  Defective myosin VIIA gene responsible for Usher syndrome type IB , 1995, Nature.

[21]  Eberhart Zrenner,et al.  Standard for clinical electroretinography , 1989, Documenta Ophthalmologica.

[22]  X. Liu,et al.  Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. , 2005, Human molecular genetics.

[23]  M. Bitner-Glindzicz,et al.  Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. , 2001, American journal of human genetics.

[24]  M. Seeliger,et al.  Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D , 2001, Nature genetics.

[25]  L. Maquat The power of point mutations , 2001, Nature Genetics.