title: Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.
abstract: The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.
authors.affiliation: Department of Medical Biosciences/Medical and Clinical Genetics, University of Umeå, Umeå, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Köhn
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.forename: Lori
authors.initials: L
authors.lastname: S Sullivan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
authors.forename: Marie S I
authors.initials: MS
authors.lastname: Burstedt
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kadzhaev
authors.forename: Ola
authors.initials: O
authors.lastname: Sandgren
authors.forename: Irina
authors.initials: I
authors.lastname: Golovleva
mesh_terms: D000293:Adolescent; D000328:Adult; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D016133:Polymerase Chain Reaction / Q000379:methods; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D013548:Sweden
chemical_list: D005136:Eye Proteins; C454222:PRPF31 protein, human