The kyphoscoliosis (ky) mouse is deficient in hypertrophic responses and is caused by a mutation in a novel muscle-specific protein

Abstract

The ky mouse mutant exhibits a primary degenerative myopathy preceding chronic thoraco-lumbar kyphoscoliosis. The histopathology of the ky mutant suggests that Ky protein activity is crucial for normal muscle growth and function as well as the maturation and stabilization of the neuromuscular junction. Muscle hypertrophy in response to increasing demand is deficient in the ky mutant, whereas adaptive fibre type shifts take place. The ky locus has previously been localized to a small region of mouse chromosome 9 and we have now identified the gene and the mutation underlying the kyphoscoliotic mouse. The ky transcript encodes a novel protein that is detected only in skeletal muscle and heart. The identification of the ky gene will allow detailed analysis of the impact of primary myopathy on idiopathic scoliosis in mice and man.

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

“…3 The Ky gene was identified in 2001 by positional cloning, and a novel muscle-specific protein was identified. 5 The KY protein harbors a transglutaminase/protease domain, which is homologous to other proteins in the transglutaminase family, and it has been proposed to be a protease. 5,6 However, multiple alignment with proteins belonging to the transglutaminase superfamily showed that a group of transglutaminase proteins including KY lack the enzymatic active site triad of amino acids, and the protease function has been questioned.…”

“…5 The KY protein harbors a transglutaminase/protease domain, which is homologous to other proteins in the transglutaminase family, and it has been proposed to be a protease. 5,6 However, multiple alignment with proteins belonging to the transglutaminase superfamily showed that a group of transglutaminase proteins including KY lack the enzymatic active site triad of amino acids, and the protease function has been questioned. 13,18 Futher studies indicates that KY should be considered to be a Z-discassociated structural protein that interacts with sarcomeric partners such as filamin C (FLNC), myosin binding protein C, slow type (MYBPC1), KY interacting protein 1 (KYIP1, IGFN1) and titin (TTN).…”

“…4 The causative variant, a GC deletion in Ky resulting in frameshift and a premature stop codon, was identified by a positional cloning strategy. 5 The ky transcript codes for a musclespecific protein and is only expressed in skeletal and cardiac muscle in mice. 5 The KY protein belongs to a family of transglutaminase-like proteins.…”

“…5 The ky transcript codes for a musclespecific protein and is only expressed in skeletal and cardiac muscle in mice. 5 The KY protein belongs to a family of transglutaminase-like proteins. 5,6 However, recent data indicate that KY should be considered a Z-disc-associated protein that provides structural support.…”

“…5 The KY protein belongs to a family of transglutaminase-like proteins. 5,6 However, recent data indicate that KY should be considered a Z-disc-associated protein that provides structural support. 7 Here we report the first human case of a neuromuscular disease associated with a variant in KY.…”