Novel mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures.

BACKGROUND

The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in has recently been reported in two families with a severe muscle and bone disorder.

OBJECTIVE

We aim to contribute to a better understanding of the ASCC1-related disorder.

METHODS

Here, we provide a clinical, histological and genetic description of three additional ASCC1 families.

RESULTS

All patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in , including two novel mutations.

CONCLUSION

Overall, this work expands the mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.

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