title: An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy.
abstract: OBJECTIVE
  To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family.
  
  
  METHODS
  Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing.
  
  
  RESULTS
  The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous 10 bp deletion between positions -26 and -17 (c.2281-26_-17del). The deletion was linked to a known SNP, c.2281-6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281-26_-17del leads to complete exon 22 skipping.
  
  
  CONCLUSIONS
  A novel and unique intronic mutation of PROM1, underlying autosomal recessive CRD in a consanguineous Israeli family, was found. This report expands the spectrum of pathogenic mutations of PROM1 and further demonstrates the importance of intronic mutations.
authors.affiliation: Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Eidinger
authors.affiliation: Alberto Moscona Department of Ophthalmology, Rambam Health Care Center, Haifa, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Leibu
authors.affiliation: Department of Ophthalmology, Tel-Aviv Souraski Medical Center, Tel-Aviv, Israel ; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Newman
authors.affiliation: Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Leah
authors.initials: L
authors.lastname: Rizel
authors.affiliation: Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel ; Department of Ophthalmology, Tel-Aviv Souraski Medical Center, Tel-Aviv, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Perlman
authors.affiliation: Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Yosef
mesh_terms: D000071916:AC133 Antigen; D000293:Adolescent; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D004596:Electroretinography; D005074:Evoked Potentials, Visual; D005260:Female; D005808:Genes, Recessive; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007438:Introns; D007557:Israel; D007585:Jews / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D010455:Peptides / Q000737:chemistry / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014429:Twins, Dizygotic
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D004247:DNA