Tcap/telethonin encodes a Z-disc
protein that plays important roles in sarcomere assembly, sarcomere-membrane interaction and stretch sensing. It remains unclear why mutations in
Tcap lead to
limb-girdle muscular dystrophy 2G (
LGMD2G) in human patients. Here, we cloned
tcap in zebrafish and conducted genetic studies. We show that
tcap is functionally conserved, as the
Tcap protein appears in the sarcomeric Z-disc and reduction of
Tcap resulted in
muscular dystrophy-like phenotypes including deformed muscle structure and impaired swimming ability. However, the observations that
Tcap integrates into the sarcomere at a stage after the Z-disc becomes periodic, and that the sarcomere remains intact in
tcap morphants, suggest that defective sarcomere assembly does not contribute to this particular type of
muscular dystrophy. Instead, a defective interaction between the sarcomere and plasma membrane was detected, which was further underscored by the disrupted development of the T-tubule system. Pertinent to a potential function in stretch sensor signaling, zebrafish
tcap exhibits a variable expression pattern during somitogenesis. The variable expression is inducible by stretch force, and the expression level of
Tcap is negatively regulated by
integrin-link
kinase (ILK), a
protein kinase that is involved in stretch sensing signaling. Together, our genetic studies of
tcap in zebrafish suggested that pathogenesis in
LGMD2G is due to a disruption of sarcomere-T-tubular interaction, but not of sarcomere assembly per se. In addition, our data prompted a novel hypothesis that predicts that the transcription level of
Tcap can be regulated by the stretch force to ensure proper sarcomere-membrane interaction in striated muscles.