PD Dr.rer nat Andreas Roos (Essen / DE), PD Dr. med Heike Kölbel (Essen / DE), Prof. Dr. Angela Abicht (München / DE), Dr. Andreas Hentschel (Dortmund / DE), Prof. Dr. med Ulrike Schara-Schmidt (Essen / DE), Prof. Dr. Cornelia Kornblum (Bonn / DE), Univ.-Prof. Dr. med. Joachim Weis (Aachen / DE), Dr. med. Jens Reimann (Bonn / DE)
Abstract-Text (inkl. Referenzen)
Background:Troponin I, fast skeletal muscle (TNNI2 encoded by the TNNI2 gene) is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to muscle actomyosin ATPase activity. Thus, TNNI2 is involved in function and integrity of sarcomeres. Multiple dominant pathogenic variants in TNNI2 (assumed to be a gain of function) are associated with congenital distal arthrogryposis.
Methods:Exome sequencing was performed to identify the cause of a congenital myopathy (without arthrogryposis and cardiac symptoms) in a 15-years old girl. Muscle biopsy studies included histology, electron microscopy, proteomic profiling and immunofluorescence.
Results:Molecular genetics revealed a homozygous TNNI2 variant (c.9-1G>C). Microscopic studies of the muscle biopsy underlined the myopathic changes including sarcomeric disintegration. Proteomic signature of muscle revealed decreased TNNI2 level accompanied by dysregulation of proteins beyond cytoskeleton. Immunofluorescence studies of paradigmatic proteins confirmed proteomic findings.
Conclusions:Our combined data add TNNI2 to the list of recessive genes associated with congenital myopathy and to the list of neuromuscular genes following both, dominant and recessive modes of inheritance. Biochemical findings indicate a loss of function mechanism, provided comprehensive insights into the biochemical nature of the disease, and introduced the first proteome for TNNI2opathies described thus far