Titin Diversity—Alternative Splicing Gone Wild

Abstract

Titin is an extremely large protein found in highest concentrations in heart and skeletal muscle. The single mammalian gene is expressed in multiple isoforms as a result of alternative splicing. Although titin isoform expression is controlled developmentally and in a tissue specific manner, the vast number of potential splicing pathways far exceeds those described in any other alternatively spliced gene. Over 1 million human splice pathways for a single individual can be potentially derived from the PEVK region alone. A new splicing pattern for the human cardiac N2BA isoform type has been found in which the PEVK region includes only the N2B type exons. The alterations in splicing and titin isoform expression in human heart disease provide impetus for future detailed study of the splicing mechanisms for this giant protein.

Genome-Wide Association Study of MKI67 Expression and its Clinical Implications in HBV-Related Hepatocellular Carcinoma in Southern China

“…Alternative splicing of the gene results in multiple transcript variants. The mechanisms controlling TTN splicing remain unknown, but the ability to manipulate the splicing of the TTN protein has great potential for affecting human health [39]. …”

Restriction of Calpain3 Expression to the Skeletal Muscle Prevents Cardiac Toxicity and Corrects Pathology in a Murine Model of Limb-Girdle Muscular Dystrophy

“…[17][18][19] Interestingly, suppression of the activity of the protease through its interaction with titin has been demonstrated experimentally at the N2A region, a region of titin tissue-specific alternative splicing. 20,21 The first strategy that we tested to prevent the cardiac toxicity was the introduction of miR-208a target sequences in the 3′-untranslated region of CAPN3 transgene. We validated the ability of miR-208a to block the expression of the transgene bearing the miR208a target.…”

Nuances of electrophoresis study of titin/connectin

“…Using human and animal skeletal muscle myosin heavy chain (205 kDa) and, nebulin (770-890 kDa), as well as the N2A titin isoform (∼3600 kDa and 3700 kDa) of rabbit and human soleus as standards Krüger et al 1991;Granzier and Wang 1993;Prado et al 2005), we estimated that the NT have a Mr of ∼3.8-3.9 × 10 6 (Vikhlyantsev and Podlubnaya 2006). Expression of titin isoforms with these molecular weights is not excluded (Bang et al 2001;Guo et al 2010Guo et al , 2012Li et al 2012), but titin aggregates in gels could not be excluded either (Granzier and Wang 1993;Cazorla et al 2000;Warren et al 2003a). Assuming that molecular masses of titin aggregates should considerably exceed 3800-3900 kDa, we decided to find out more about the differences in electrophoretic mobility of the observed bands.…”

“…Further studies showed that the titin gene (TTN) consists of 363 coding exons, which can be differentially spliced and theoretically could generate more than 1 million splice variants in striated and smooth muscles of mammals Bang et al 2001;Labeit et al 2006;Guo et al 2010;Gerull 2015).…”