Recessive myopalladin mutations cause congenital cap myopathy with unusual rods

International audienceTo identify the causative gene in three patients presenting progressive congenital myopathy and cap structures in skeletal muscle. Cap myopathy is a rare congenital myopathy characterized by the presence of peripherally-placed, well delimited structures resembling a cap in muscle fibres. Caps are mainly composed by thin filaments and segments of Z-disc. Although causative mutations in TPM2, TPM3, and ACTA1 genes have been associated with cap myopathy, an important number of patients remain without a molecular diagnosis precluding familial counselling and better patient health care. Clinical, histopathological and exome sequencing analyses were performed on three cap myopathy patients from two unrelated families. All patients, two males and one female, presented a consistent clinical phenotype characterized by neonatal hypotonia, retarded motor development and bone deformities including pectus excavatum, elongated face and high-arched palate. They successively developed severe facial weakness and progressive proximo-distal and axial muscle weakness without overt cardiomyopathy. One male patient lost ambulation in his late forties. Muscle biopsies revealed cap structures and atypical nemaline rods associated with type 1 fibers uniformity. Exome sequencing disclosed two different homozygous truncating mutations in the MYPN gene encoding for myopalladin (MYPN), a Z-disc protein implicated in sarcomere integrity. Mutations led to the truncation of the C-terminal part of MYPN responsible for the interaction with alpha-actinin. Immunostaining on frozen muscle sections with a MYPN N-terminal antibody showed strong labelling of caps and atypical rods suggesting aberrant aggregation of the truncated protein. Autosomal dominant mutations in MYPN gene have been reported in dilated, restrictive or hypertrophic cardiomyopathies (MIM#615248) without skeletal muscle involvement. Our findings demonstrate that recessive MYPN gene mutations cause cap myopathy. This suggests that MYPN is involved in two different diseases through different modes of inheritance