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Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy

Sebahattin Cirak, Florian von Deimling, Shrikesh Sachdev, Wesley J. Errington, Ralf Herrmann, Carsten Bönnemann, Knut Brockmann, Stephan Hinderlich, Tom H. Lindner, Alice Steinbrecher, Katrin Hoffmann, Gilbert G. Privé, Mark Hannink, Peter Nürnberg, Thomas Voit
DOI: http://dx.doi.org/10.1093/brain/awq108 2123-2135 First published online: 16 June 2010


Distal myopathies are a heterogeneous group of disorders characterized by progressive weakness and muscular atrophy, beginning in distal limb muscles and affecting proximal limb muscles at a later stage. We studied a large German kindred with 10 affected members. Weakness and atrophy of the anterior tibial muscles started between the ages of 8 and 16 years, followed by atrophy of intrinsic hand muscles. Progression was slow, and patients retained the ability to walk until the seventh decade. Serum creatinine kinase levels were increased in the range of 150–1400 U/l. Muscle biopsies showed myopathic changes, whereas immunohistochemistry showed normal expression of marker proteins for muscular dystrophies. Patients had reduced sensation with stocking-glove distribution in the distal limbs in later life. Nerve conduction studies revealed no evidence of neuropathy. Genome-wide linkage analysis in this family revealed a new locus for distal myopathy at 9p21.2-p22.3 (multipoint logarithm of the odds ratio = 4.21). By positional cloning we found a heterozygous mutation L95F in the Kelch-like homologue 9 gene, encoding a bric-a-brac Kelch protein. Molecular modelling indicated that the mutation may interfere with the interaction of the bric-a-brac domain with Cullin 3. Coimmunoprecipitation experiments confirmed that the mutation reduces association with Cullin 3 in the Kelch-like homologue 9-Cullin 3–E3 ubiquitin ligase complex, which is involved in ubiquitin-dependent protein degradation. We identified a unique form of early onset autosomal dominant distal myopathy which is associated with a Kelch-like homologue 9 mutation and interferes with normal skeletal muscle through a novel pathogenetic mechanism.

  • early onset
  • distal myopathy
  • bric-a-brac-BACK-kelch protein
  • Cullin 3
  • ubiquitin ligase
  • Abbreviations:
     Cullin 3
    Human influenza hemagglutinin (HA) Tag-cullin3
     kelch-like homologue 9 gene
     reverse transcriptase polymerase chain reaction

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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