Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

Abstract

Myoglobin, encoded by MB , is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O 2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O 2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.

Pseudoperoxidase activity, conformational stability, and aggregation propensity of the His98Tyr myoglobin variant: implications for the onset of myoglobinopathy

“…From the intercept of the linear plots, the dissociation rate constants (k off ) were obtained allowing calculation of the dissociation constants, K D (= k off /k on ), which resulted 3.7 and 10.9 µM, respectively (Table 1). Ferric H98Y MB therefore features a lower affinity for cyanide compared with the wt protein, as previously observed for molecular oxygen [7].…”

An Autopsy Case of Idiopathic Rhabdomyolysis in 1979: Immunoperoxidase Detection of Myoglobin Casts in Formalin-Fixed, Paraffin-Embedded Sections of the Kidney

“…The Danish man first manifested in an airplane, so that the possibility of “myoglobinopathy” was considered. A recently reported disease entity myoglobinopathy shows progressive chronic myopathy with an autosomal-dominant trait [ 6 ], but an acute disease as seen in the present case has not been described.…”

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

“…Weekly interdisciplinary meetings between the clinical, scientific, neuropathological, and research teams were vital for maximizing diagnostic success and triage of unsolved patients to research projects, as reported by others . This process facilitated the discovery of six new disease genes …”

“…10,20,21 This process facilitated the discovery of six new disease genes. [22][23][24][25][26][27] Use of a large panel, rather than exome sequencing, provided the optimal balance between cost and diagnostic success. Panel sequencing costs less than exome sequencing and has only 4-11% lower success rates than exomes restricted to known genes.…”