title: Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G-->A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Friedman
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Ray
authors.forename: Naushin
authors.initials: N
authors.lastname: Waseem
authors.forename: Kory
authors.initials: K
authors.lastname: Johnson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brooks
authors.forename: Therése
authors.initials: T
authors.lastname: Hugosson
authors.forename: Debra
authors.initials: D
authors.lastname: Breuer
authors.forename: Kari E
authors.initials: KE
authors.lastname: Branham
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Krauth
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.forename: Vesna
authors.initials: V
authors.lastname: Ponjavic
authors.forename: Lotta
authors.initials: L
authors.lastname: Gränse
authors.forename: Ritu
authors.initials: R
authors.lastname: Khanna
authors.forename: Edward H
authors.initials: EH
authors.lastname: Trager
authors.forename: Linn M
authors.initials: LM
authors.lastname: Gieser
authors.forename: Dianna
authors.initials: D
authors.lastname: Hughbanks-Wheaton
authors.forename: Radu I
authors.initials: RI
authors.lastname: Cojocaru
authors.forename: Noor M
authors.initials: NM
authors.lastname: Ghiasvand
authors.forename: Christina F
authors.initials: CF
authors.lastname: Chakarova
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrahamson
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Goncalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Yang
authors.initials: Y
authors.lastname: Fann
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Sten
authors.initials: S
authors.lastname: Andréasson
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D001324:Autoantigens; C505353:KLHL7 protein, human