title: Nonsense-mediated decay as the molecular cause for autosomal recessive bestrophinopathy in two unrelated families.
abstract: OBJECTIVE
  To characterize the molecular basis of two novel BEST1 mutations causing autosomal recessive bestrophinopathy (ARB). Strong evidence argues in favor of the dominant negative effects of most autosomal dominantly inherited mutations, whereas there is only weak support for the molecular basis of the ARB phenotype.
  
  
  METHODS
  Patients underwent ophthalmic examination, color and autofluorescence fundus imaging, optical coherence tomography (OCT), electrooculogram, and full-field electroretinogram (ERG). BEST1 was directly screened for mutations in two ARB unrelated patients. The pathogenicity of the new BEST1 variants was assessed in silico and in vivo.
  
  
  RESULTS
  Two unrelated patients with diagnoses of ARB showed retinal pigment epithelial disturbances and abnormal ERGs. Each patient was homozygous for a novel BEST1 mutation, c.521_522del and c.1100+1G>A. A carrier sibling (WT/c.521_522del) was unaffected. Both mutations generate a frameshift and a premature stop codon that, if translated, would seriously compromise bestrophin-1 function. However, the in vivo quantitative RT-PCR assays showed that most of the mutated transcripts were eliminated before translation because the mRNA-BEST1 levels were dramatically diminished the controls.
  
  
  CONCLUSIONS
  In truncating BEST1 mutations, the null phenotype associated with ARB is attributed to a substantial decrease of BEST1 expression promoted by the nonsense-mediated decay (NMD) surveillance mechanism. Moreover, the severity of the phenotype increases with the preserved amount of altered transcript, suggesting that the clinical outcome reflects the combined null and dominant negative effects of the two mutations over the patient's genetic background.
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pomares
authors.forename: Anniken
authors.initials: A
authors.lastname: Burés-Jelstrup
authors.forename: Sheila
authors.initials: S
authors.lastname: Ruiz-Nogales
authors.forename: Borja
authors.initials: B
authors.lastname: Corcóstegui
authors.forename: Roser
authors.initials: R
authors.lastname: González-Duarte
authors.forename: Rafael
authors.initials: R
authors.lastname: Navarro
mesh_terms: D000293:Adolescent; D000075002:Bestrophins; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004585:Electrooculography; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005808:Genes, Recessive / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D041623:Tomography, Optical Coherence
chemical_list: C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins; D004247:DNA