title: Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy.
abstract: 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.
authors.affiliation: Institute of Child Health, Dubowitz Neuromuscular Centre, 30 Guilford Street, London WC1N1EH, UK. s.cirak@ich.ucl.ac.uk
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Florian
authors.initials: F
authors.lastname: von Deimling
authors.forename: Shrikesh
authors.initials: S
authors.lastname: Sachdev
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: Errington
authors.forename: Ralf
authors.initials: R
authors.lastname: Herrmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Bönnemann
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Hinderlich
authors.forename: Tom H
authors.initials: TH
authors.lastname: Lindner
authors.forename: Alice
authors.initials: A
authors.lastname: Steinbrecher
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Gilbert G
authors.initials: GG
authors.lastname: Privé
authors.forename: Mark
authors.initials: M
authors.lastname: Hannink
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049310:Distal Myopathies / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000503:physiopathology; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C473356:KLHL6 protein, human