title: Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.
abstract: BACKGROUND
  Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth.
  
  
  RESULTS
  To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele.
  
  
  CONCLUSIONS
  One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Schultz
authors.forename: Rashid
authors.initials: R
authors.lastname: Bhatti
authors.forename: Anne C
authors.initials: AC
authors.lastname: Madeo
authors.forename: Amy
authors.initials: A
authors.lastname: Turriff
authors.forename: Julie A
authors.initials: JA
authors.lastname: Muskett
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Zalewski
authors.forename: Kelly A
authors.initials: KA
authors.lastname: King
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Nazir
authors.initials: N
authors.lastname: Ahmad
authors.forename: Zawar
authors.initials: Z
authors.lastname: Hussain
authors.forename: Muhammad
authors.initials: M
authors.lastname: Qasim
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Kahn
authors.forename: Meira R
authors.initials: MR
authors.lastname: Meltzer
authors.forename: Xue Z
authors.initials: XZ
authors.lastname: Liu
authors.forename: Murali
authors.initials: M
authors.lastname: Munisamy
authors.forename: Manju
authors.initials: M
authors.lastname: Ghosh
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.forename: Ekaterini T
authors.initials: ET
authors.lastname: Tsilou
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
authors.forename: Wadih M
authors.initials: WM
authors.lastname: Zein
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Brewer
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D058070:Asymptomatic Diseases; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D014481:United States; D052245:Usher Syndromes / Q000235:genetics* / Q000473:pathology; D014722:Vestibule, Labyrinth / Q000378:metabolism* / Q000473:pathology; D044465:White People / Q000235:genetics
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins