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

James S. Friedman, Joseph 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 journalArticle

63 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)792-800
Number of pages9
JournalAmerican Journal of Human Genetics
Volume84
Issue number6
DOIs
StatePublished - Jun 12 2009
Externally publishedYes

Fingerprint

Retinitis Pigmentosa
Retinal Rod Photoreceptor Cells
Mutation
Ubiquitination
Giant Axonal Neuropathy
Proteins
Cullin Proteins
Retinal Cone Photoreceptor Cells
Vertebrate Photoreceptor Cells
Ubiquitin-Protein Ligases
Missense Mutation
Proteasome Endopeptidase Complex
Ubiquitin
Neurodegenerative Diseases
Proteolysis
Genes
Retina
Exons
Chromosomes
Amino Acids

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Friedman, J. S., Ray, J., Waseem, N., Johnson, K., Brooks, M. J., Hugosson, T., ... Swaroop, A. (2009). Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa. American Journal of Human Genetics, 84(6), 792-800. https://doi.org/10.1016/j.ajhg.2009.05.007

Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa. / Friedman, James S.; Ray, Joseph; Waseem, Naushin; Johnson, Kory; Brooks, Matthew J.; Hugosson, Therése; Breuer, Debra; Branham, Kari E.; Krauth, Daniel S.; Bowne, Sara J.; Sullivan, Lori S.; Ponjavic, Vesna; Gränse, Lotta; Khanna, Ritu; Trager, Edward H.; Gieser, Linn M.; Hughbanks-Wheaton, Dianna; Cojocaru, Radu I.; Ghiasvand, Noor M.; Chakarova, Christina F.; Abrahamson, Magnus; Göring, Harald H H; Webster, Andrew R.; Birch, David G.; Abecasis, Goncalo R.; Fann, Yang; Bhattacharya, Shomi S.; Daiger, Stephen P.; Heckenlively, John R.; Andréasson, Sten; Swaroop, Anand.

In: American Journal of Human Genetics, Vol. 84, No. 6, 12.06.2009, p. 792-800.

Research output: Contribution to journalArticle

Friedman, JS, Ray, J, Waseem, N, Johnson, K, Brooks, MJ, Hugosson, T, Breuer, D, Branham, KE, Krauth, DS, Bowne, SJ, Sullivan, LS, Ponjavic, V, Gränse, L, Khanna, R, Trager, EH, Gieser, LM, Hughbanks-Wheaton, D, Cojocaru, RI, Ghiasvand, NM, Chakarova, CF, Abrahamson, M, Göring, HHH, Webster, AR, Birch, DG, Abecasis, GR, Fann, Y, Bhattacharya, SS, Daiger, SP, Heckenlively, JR, Andréasson, S & Swaroop, A 2009, 'Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa', American Journal of Human Genetics, vol. 84, no. 6, pp. 792-800. https://doi.org/10.1016/j.ajhg.2009.05.007
Friedman, James S. ; Ray, Joseph ; Waseem, Naushin ; Johnson, Kory ; Brooks, Matthew J. ; Hugosson, Therése ; Breuer, Debra ; Branham, Kari E. ; Krauth, Daniel S. ; Bowne, Sara J. ; Sullivan, Lori S. ; Ponjavic, Vesna ; Gränse, Lotta ; Khanna, Ritu ; Trager, Edward H. ; Gieser, Linn M. ; Hughbanks-Wheaton, Dianna ; Cojocaru, Radu I. ; Ghiasvand, Noor M. ; Chakarova, Christina F. ; Abrahamson, Magnus ; Göring, Harald H H ; Webster, Andrew R. ; Birch, David G. ; Abecasis, Goncalo R. ; Fann, Yang ; Bhattacharya, Shomi S. ; Daiger, Stephen P. ; Heckenlively, John R. ; Andréasson, Sten ; Swaroop, Anand. / Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa. In: American Journal of Human Genetics. 2009 ; Vol. 84, No. 6. pp. 792-800.
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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.",
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T1 - Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

AU - Friedman, James S.

AU - Ray, Joseph

AU - Waseem, Naushin

AU - Johnson, Kory

AU - Brooks, Matthew J.

AU - Hugosson, Therése

AU - Breuer, Debra

AU - Branham, Kari E.

AU - Krauth, Daniel S.

AU - Bowne, Sara J.

AU - Sullivan, Lori S.

AU - Ponjavic, Vesna

AU - Gränse, Lotta

AU - Khanna, Ritu

AU - Trager, Edward H.

AU - Gieser, Linn M.

AU - Hughbanks-Wheaton, Dianna

AU - Cojocaru, Radu I.

AU - Ghiasvand, Noor M.

AU - Chakarova, Christina F.

AU - Abrahamson, Magnus

AU - Göring, Harald H H

AU - Webster, Andrew R.

AU - Birch, David G.

AU - Abecasis, Goncalo R.

AU - Fann, Yang

AU - Bhattacharya, Shomi S.

AU - Daiger, Stephen P.

AU - Heckenlively, John R.

AU - Andréasson, Sten

AU - Swaroop, Anand

PY - 2009/6/12

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