What causes nemaline myopathy 1 (NEM1)?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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Answer

NEM1 is due to a mutation in the gene for α-tropomyosin 3 (TPM3). This is likely a rare cause (< 3%) of nemaline myopathy, but variants in TPM3 can also cause a congenital fiber-type disproportion myopathy subytpe. [7]  Tropomyosins are a family of actin-binding coiled-coil proteins that help to regulate calcium-dependent muscle contraction. Multiple isoforms exist, with three striated muscle isoforms: α-tropomyosinfast (TPM1), β-tropomyosin (TPM2), and α-tropomyosinslow (TPM3). In muscle, the heterodimers α-tropomyosinslow–β-tropomyosin (slow twitch) and α-tropomyosinfast–β-tropomyosin (fast twitch) are most common.

In human and animal studies of a dominant mutation of TPM3, a number of functional defects were noted. There was reduced affinity for F-actin, reduced formation of preferred α/β heterodimers in favor of α/α heterodimers, destabilization of the coiled coil, impaired binding to tropomodulin, and reduced sensitivity of isometric force production to activating calcium. [8, 9, 10]

Autosomal dominant inheritance is usually due to a missense mutation and causes a moderate phenotype with onset between birth and 15 years of age. Weakness is diffuse and symmetric with slow progression often with need for a wheelchair in adulthood. Respiratory failure is common. Other features include kyphoscoliosis and a thin body habitus.

Autosomal recessive inheritance is usually due to a nonsense mutation causing a stop codon. Onset is at birth with moderate-to-severe hypotonia and diffuse weakness. In the most severe cases, death can occur before 2 years of age. Less severe cases have delayed major motor milestones, and these patients may walk, but often need a wheelchair before 10 years of age.

In autosomal recessive cases in which no functional α-tropomyosin is present, altered ratios of the remaining sarcomeric proteins may be sufficient to cause the formation of rods.


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