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

Abstract

We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder -but in contrast, no kyphoscoliosis.

Transcriptional upregulation of Bag3, a chaperone-assisted selective autophagy factor, in animal models of KY-deficient hereditary myopathy

“…3 C). We conclude that the absence of Ky in zebrafish does not have the same effect on muscle morphology or fibre type as seen in ky mutant mice ( Blanco et al, 2001 ) or in patients with KY-associated myopathy ( Hedberg-Oldfors et al, 2016 ). Analysis of the molecular effects of KY deficiency provided some evidence of functional conservation, however.…”

“…We cannot rule out that other tests (e.g. electron microscopy or analysis of the expression of embryonic myosin isoform in adult muscle, as observed in human patients; Hedberg-Oldfors et al, 2016 ) might reveal myopathic phenotypes in the embryonic zebrafish model. Likewise, experiments challenging adult ky yo1 / ky yo1 zebrafish muscle could also reveal myopathic phenotypes.…”

“…Disruptive mutations in the Ky gene result in overt muscle pathology in mice ( Bridges et al, 1992 ) and humans ( Hedberg-Oldfors et al, 2016 ; Straussberg et al, 2016 ; Yogev et al, 2017 ). Impaired FLNC turnover is a commonly reported molecular phenotype in mice and humans, which potentially implicates CASA in the pathogenic mechanism.…”

“…Mutations in the KY gene associated with myopathy have been recently reported in human patients ( Hedberg-Oldfors et al, 2016 ; Straussberg et al, 2016 ; Yogev et al, 2017 ). Common pathological hallmarks in mice and humans include muscle atrophy of the soleus and the presence of FLNC aggregates.…”

Proteomic resolution of IGFN1 complexes reveals a functional interaction with the actin nucleating protein COBL

“…Subsequently, both proteins were localized at the Z-disc [ 2 ]. Mutations in the ky gene cause muscle disease in mice and humans [ [3] , [4] , [5] , [6] ], indicating a crucial role for the corresponding protein in skeletal muscle. KY has recently been implicated in protein turnover [ 7 ], in agreement with previous reports showing accumulation of the actin binding crosslinkers filamin C and Xin in muscles from ky/ky mice [ 1 , 8 ].…”