title: Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1.
abstract: OBJECTIVE
  To identify the genetic basis of a large consanguineous Spanish pedigree affected with autosomal recessive retinitis pigmentosa (arRP) with premature macular atrophy and myopia.
  
  
  METHODS
  After a high-throughput cosegregation gene chip was used to exclude all known RP and Leber congenital amaurosis (LCA) candidates, genome-wide screening and linkage analysis were performed. Direct mutational screening identified the pathogenic mutation, and primers were designed to obtain the RT-PCR products for isoform characterization.
  
  
  RESULTS
  Mutational analysis detected a novel homozygous PROM1 mutation, c.869delG in exon 8 cosegregating with the disease. This variant causes a frameshift that introduces a premature stop codon, producing truncation of approximately two-thirds of the protein. Analysis of PROM1 expression in the lymphocytes of patients, carriers, and control subjects revealed an aberrant transcript that is degraded by the nonsense-mediated decay pathway, suggesting that the disease is caused by the absence of the PROM1 protein. Three (s2, s11 and s12) of the seven alternatively spliced isoforms reported in humans, accounted for 98% of the transcripts in the retina. Given that these three contained exon 8, no PROM1 isoform is expected in the affected retinas.
  
  
  CONCLUSIONS
  A remarkable clinical finding in the affected family is early macular atrophy with concentric spared areas. The authors propose that the hallmark of PROM1 truncating mutations is early and severe progressive degeneration of both rods and cones and highlight this gene as a candidate of choice to prioritize in the molecular genetic study of patients with noncanonical clinical peripheral and macular affectation.
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Jon
authors.initials: J
authors.lastname: Permanyer
authors.forename: Rafael
authors.initials: R
authors.lastname: Navarro
authors.forename: James
authors.initials: J
authors.lastname: Friedman
authors.forename: Esther
authors.initials: E
authors.lastname: Pomares
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castro-Navarro
authors.forename: Gemma
authors.initials: G
authors.lastname: Marfany
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Roser
authors.initials: R
authors.lastname: Gonzàlez-Duarte
mesh_terms: D000071916:AC133 Antigen; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D001284:Atrophy; D018389:Codon, Nonsense / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009216:Myopia / Q000235:genetics; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D012160:Retina / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D041623:Tomography, Optical Coherence; D014794:Visual Fields
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018389:Codon, Nonsense; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides