Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa.
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.
Friedman
James S
JS
Neurobiology-Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Ray
Joseph W
JW
Waseem
Naushin
N
Johnson
Kory
K
Brooks
Matthew J
MJ
Hugosson
Therése
T
Breuer
Debra
D
Branham
Kari E
KE
Krauth
Daniel S
DS
Bowne
Sara J
SJ
Sullivan
Lori S
LS
Ponjavic
Vesna
V
Gränse
Lotta
L
Khanna
Ritu
R
Trager
Edward H
EH
Gieser
Linn M
LM
Hughbanks-Wheaton
Dianna
D
Cojocaru
Radu I
RI
Ghiasvand
Noor M
NM
Chakarova
Christina F
CF
Abrahamson
Magnus
M
Göring
Harald H H
HH
Webster
Andrew R
AR
Birch
David G
DG
Abecasis
Goncalo R
GR
Fann
Yang
Y
Bhattacharya
Shomi S
SS
Daiger
Stephen P
SP
Heckenlively
John R
JR
Andréasson
Sten
S
Swaroop
Anand
A
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
D001324:Autoantigens; C505353:KLHL7 protein, human