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Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Summary: ARTICLE
Mutations in a BTB-Kelch Protein, KLHL7,
Cause Autosomal-Dominant Retinitis Pigmentosa
James S. Friedman,1 Joseph W. Ray,2 Naushin Waseem,3 Kory Johnson,4 Matthew J. Brooks,1
There´se Hugosson,5 Debra Breuer,6 Kari E. Branham,6 Daniel S. Krauth,1 Sara J. Bowne,2
Lori S. Sullivan,2 Vesna Ponjavic,5 Lotta Gra¨nse,5 Ritu Khanna,6 Edward H. Trager,6 Linn M. Gieser,1
Dianna Hughbanks-Wheaton,7 Radu I. Cojocaru,1 Noor M. Ghiasvand,6,12 Christina F. Chakarova,3
Magnus Abrahamson,8 Harald H.H. Go¨ring,9 Andrew R. Webster,3 David G. Birch,7
Goncalo R. Abecasis,10 Yang Fann,4 Shomi S. Bhattacharya,3 Stephen P. Daiger,2 John R. Heckenlively,6
Sten Andre´asson,5 and Anand Swaroop1,6,11,*
Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunc-
tion 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 iden-
tify 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


Source: Abecasis, Goncalo - Department of Biostatistics, University of Michigan


Collections: Biology and Medicine; Mathematics