Biallelic Mutations in MYPN , Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy

Abstract

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance

“…Intranuclear rods, which are known to be associated with severe-infantile form of nemaline myopathy with ACTA1 mutation and relatively mild form with MYPN mutation, has been rarely reported [2,4,8,36]. It should be noted that NB per se is not specific although its presence is a mandatory finding of nemaline myopathies.…”

“…Currently, nemaline myopathy is regarded as a heterogeneous disease entity. Most of the cases show child-onset and usually chronic progressive course with autosomal recessive or dominant inheritance pattern, and now at least 11 causative genes are identified: TPM3, NEB, ACTA1, TPM2, TNNT1, KBTBD13, CFN2, KLHL40, KLHL41, LMOD3, and MYPN [2]. Meanwhile, adult-onset form is also occasionally seen.…”

Expanding the histopathological spectrum of CFL2‐related myopathies

“…1 So far, mutations in 12 different genes have been reported to cause autosomal dominant (AD) or autosomal recessive (AR) forms of NM. [2][3][4][5][6][7][8][9][10][11][12][13][14] Cofilin-2 is a widely expressed member of the AC group of proteins that regulate actin-filament dynamics. 15 It binds to and depolymerizes filamentous F-actin, and negatively controls polymerization of monomeric G-actin in a pH-dependent manner.…”

Myopalladin promotes muscle growth through modulation of the serum response factor pathway

“…The MKO mouse model is particularly relevant in light of the recent identification of biallelic loss‐of‐function mutations associated with NM, cap myopathy, and congenital myopathy with hanging big toe and ultrastructural changes, including Z‐line fragmentation and disruption of the regular square pattern of the Z‐line, possible early manifestations of Z‐line destabilization . TEM of MKO muscle showed normal sarcomere organization without nemaline rod bodies or caps.…”

“…1,5 Heterozygous dominant negative MYPN gene mutations are associated with human hypertrophic, dilated, and restrictive cardiomyopathy (RCM). [6][7][8][9] Furthermore, homozygous loss-of-function MYPN truncating mutations (nonsense, frameshift, or splice-site mutations), resulting in reduced MYPN expression, were recently identified in patients with slowly progressive cap myopathy, 10 a relatively mild form of slowly progressive nemaline myopathy (NM) with or without intranuclear rods, 11 and mildly progressive congenital myopathy with hanging big toe. 12 This demonstrates the importance of MYPN in striated muscle, although its function has remained elusive.…”