NEW GENES, NEW TECHNIQUES IN NEUROMUSCULAR DISORDERS: O.10 Loss of function mutations in DNAJB4 cause a myopathy with early respiratory failure

Abstract

Through next generation sequencing of patients with unexplained muscle disease, we identified four individuals from three unrelated families carrying homozygous variants in the DNAJB4 gene. Clinical presentation was similar with acute respiratory failure leading to life threatening hypercapnia and artificial ventilation. In addition, all patients presented some degree of spine rigidity. Disease onset was variable, between the 1st and 4th decade of life. MRI showed a similar selective pattern of muscle involvement. DNAJB4 is a heat shock protein belonging to the DNAJ/HSP40 family. DNAJ proteins are emerging as proteins critical for muscle protein homeostasis and another homologous protein, DNAJB6 – is causative for LGMD D1 (DNAJB6 related). LGMDD1 is characterized by proximal and/or distal muscle weakness, atrophy and protein aggregates, myofibrillar degeneration, and rimmed vacuoles on muscle biopsy. The DNAJB4 variants identified, a stop gain (c.856A>T; p.Lys286*) and two missense changes (c.74G>A; p.Arg25Gln and c.785T>C; p.Leu262Ser) are absent in the control population and are predicted to result in loss of protein, or protein function. Consistent with this, immunoblots from patient muscle tissue and fibroblasts confirmed the absence of DNAJB4 in the p.Lys286* and p.Leu262Ser patients. Functional studies confirm that the p.Lys286* and p.Leu262Ser variants are rapidly degraded in cells. In contrast the p.Arg25Gln is stable but behaves as a loss of function in cellular assays of DNAJB4 chaperone function. In muscle DNAJB4 localizes to the Z-disc and DNAJB4 knockout myotubes and mouse muscle accumulate desmin and other potential client proteins. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function mutations may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.