Core-rod myopathy due to a novel mutation in BTB/POZ domain of KBTBD13 manifesting as late onset LGMD

Figures

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  Fig. 1. Clinical and histological findings. Picture of the patient (a): note the generalized muscle hypertrophy. Whole body muscle CT scan (b): characteristic “inside-to outside” involvement of the thighs (box); zebra pattern (arrows) of gluteus maximus; “central shadow” of rectus femoris (arrowheads); fibro-fatty replacement is also present in deltoids, subscapularis and infraspinatus, serratus, latissimus dorsi, cervical paraspinalis and rectus abdominis, iliopsoas, tensor fascia lata and gluteus maximus with while lower leg muscles are spared. Deltoid muscle biopsy at 60 years (c): rare cluster of subsarcolemmal rods (GT) and prevalence and hypotrophy of type1 fibres (NADH). Paraspinal muscle biopsy at 61 years (d): several fibres showing cytoplasmic and subsarcolemmal rods (GT) and irregular shaped areas devoid oxidative stain (COX/SDH)

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  Fig. 2. Histological and ultrastructural findings of the last muscle biopsy. Quadriceps muscle biopsy at 65 years. Sharply demarked cores in seriated sections at GT (a) and NADH (b). Cores and lobulated fibres with irregular myofibrillar network at SDH (c). Electron microscopy findings: cores containing abundant electrodense smeared material (d and e, asterisk); small rods (f,arrowheads); fragments of thickened Z-line (g); smaller areas of sarcomeric disorganization with Z-line smearing (h)

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  Fig. 3. Schematic view of KBTBD13 and functional essays. Schematic view of KBTBD13 transcript (a) showing BTB and Kelch-repeat domains. Kelch domain is composed by five repeats. First and last aminoacidic residues of both domains are also reported. The novel G67R mutation (bold red) in BTB domain and the three previously described mutations (dark blue) in Kelch domain. WB of KBTBD13 (b) showing the reduced protein expression in patient’s muscle biopsy (pt) compared to healthy controls (ctrl). Representative confocal microscopy images of HeLa cells transfected with KBTBD13WT and KBTBD13G67R pCMV6-AC-GFP plasmids. Nuclei were counterstained with 4,6-diamidino-2-phenylindole (DAPI). Scale bars: 10 μm. No difference between wild type-KBTBD13 and G67R-KBTBD13 expression and localization in HeLa transfected cells (c). Molecular models (D) of WT and mutated KBTBD13. In the upper left panel, interaction of two homodimer BTB domains (light blue and green, respectively) of two KBTBD13 molecules (not shown) as obtained by molecular modelling. The protein backbone atoms are represented as ribbons, while the two Gly67 side chains are shown as Van der Waals spheres and circled in red. The upper right…