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

James S. Friedman, Joseph W. Ray, Naushin Waseem, Kory Johnson, Matthew J. Brooks, Therése Hugosson, Debra Breuer, Kari E. Branham, Daniel S. Krauth, Sara J. Bowne, Lori S. Sullivan, Vesna Ponjavic, Lotta Gränse, Ritu Khanna, Edward H. Trager, Linn M. Gieser, Dianna Hughbanks-Wheaton, Radu I. Cojocaru, Noor M. Ghiasvand, Christina F. ChakarovaMagnus Abrahamson, Harald H.H. Göring, Andrew R. Webster, David G. Birch, Goncalo R. Abecasis, Yang Fann, Shomi S. Bhattacharya, Stephen P. Daiger, John R. Heckenlively, Sten Andréasson, Anand Swaroop

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)792-800
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - Jun 12 2009
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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