Ubiquitin-Proteasome pathway alteration in distal myopathy due to a mutation in a novel kelch protein

A kelch protein is mutated in a new autosomal dominant distal myopathy with onset between 8–16y in large German kindred. First complaints were weakness and atrophy of the anterior tibial muscles, followed by atrophy of intrinsic hand muscles, with CK levels up to 1400U/l. The motor nerve conduction velocity was decreased in the third decade, with a decrease of sensation in legs and feet's, progress was slow and ambulation was preserved till later age. Muscle biopsies demonstrated a myopathic process. Immunohistochemistry showed normal expression of dysferlin, titin, caveolin, dystrophin, alpha-, beta-, gamma- and delta-sacroglycan, emerin, laminin-alpha2 and integrin-alpha7, calpain 3. Telethonin and dysferlin were normal on western blot. A genome scan revealed a new locus at 9p22.3-p21.2 with a multipoint LOD score of Zmax=4.21 in the interval between D9S1870 and D9S161. A heterozygous mutation L95F was found in the BTB-domain of KLHL9, a Kelch protein, and showing co- segregation with the disease phenotype. We tested 300 unrelated healthy individuals and no mutation was found. BTB-domain containing proteins bridge their substrate proteins to cullin in Cul3-based E3 ubiquitin ligases. Activation of ubiquitin-proteasome pathway by muscle specific ubiquitin ligases cause muscle atrophy. Modelling of the BTB-domain dimer indicated that L95 is adjacent to the binding side of Cul3, suggesting an alteration of interaction. The targeted protein for degradation by the KLHL9-Cul3-E3 ubiquitin ligase complex remains to be discovered.