Introduction: We identified single premature stop, splice-site or deletion TTN variants in probands with cardioskeletal phenotypes characterized by mild, progressive proximodistal weakness, with the development of dilated cardiomyopathy or other cardiac manifestations in middle age. These variants segregated in families in an autosomal dominant pattern.
Objective: To investigate mechanism of disease.
Methods: Tibialis anterior biopsies were studied via Western blot, RNASeq, EM, and muscle fiber mechanic studies in 11 cases, 10 controls, and three disease controls.
Results: Western blot revealed normal full-length and truncated titin in the in-frame deletion case (exons 346-362), but only normal titin in the out-of-frame deletion, premature stop, and splice-site cases. TTN transcript levels were reduced in the premature stop and deletion cases, but normal in the splice-site cases. Skipping of exons 347-361 was observed in the in-frame deletion case. RNA splicing patterns suggest an increased ratio of adipocytes to myocytes in the diseased muscle.
Conclusions: We present evidence for a new class of dominant skeletal muscle titinopathies, a category historically restricted to only HMERF and LGMD2J. These premature stop, splice-site or deletion variants appear to result in distinct disease mechanisms in skeletal muscle, including a dominant negative mode of action (in in-frame deletion) and possible haploinsufficiency (in premature stop, splice site, and out-of-frame deletion). This observation is in contrast to what has been reported in cardiac tissue, where premature stop variants display a dominant negative mechanism.