CONGENITAL MYOPATHIES: GENERAL AND RYR1: P.46Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures

Abstract

Congenital myopathies affect children and adults in all populations. They are genetically and clinically heterogeneous with a marked variability in severity and disease progression, and patients can manifest additional non-muscle features affecting different tissues. We established a clinically homogeneous cohort of patients with a severe condition characterized by fetal hypokinesia, neonatal hypotonia, respiratory distress, arthrogryposis, and congenital bone fractures, and all deceased shortly after birth. The biopsies of the patients displayed common histological features as fiber size variability and intense oxidative rings beneath the sarcolemma, and electron microscopy revealed disorganized myofibrils with scattered remnants of sarcomeres and enlarged Z-bands. Through exome sequencing, we identified novel recessive ASCC1 nonsense and frameshift mutations in three families with a total of six affected infants, and segregation of the mutations with the disease was confirmed in all available family members. ASCC1 codes for a protein of the tetrameric ASC-1 cointegrator complex, composed of ASCC1, ASCC2, ASCC3, and TRIP4. Transcriptional cointegrators act as coactivators or corepressors through the integration of transcription factors in multi-protein complexes, and can thereby modulate gene expression in a tissue-specific way. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe and muscle and bone disorder, allowing only a narrow view on the clinical and genetic spectrum of the disorder. Our work expands the ASCC1 mutation spectrum, and identifies subsarcolemmal oxidative rings and enlarged Z-bands as potential histopathological hallmarks of the disorder. Our findings also emphasize the physiological importance of the ASC-1 complex in fetal muscle and bone development, and pave the way for the molecular diagnosis of further ASCC1 cases.