title: 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.
authors.affiliation: Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Carola
authors.initials: C
authors.lastname: Hedberg-Oldfors
authors.affiliation: Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.affiliation: Pediatric Clinic, Blekinge Hospital, Karlskrona, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Olsson Engman
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Orfanos
authors.affiliation: Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Thomsen
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.affiliation: Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
mesh_terms: D017668:Age of Onset; D002648:Child; D018389:Codon, Nonsense; D005260:Female; D064448:Filamins / Q000378:metabolism; D006801:Humans; D007738:Kyphosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics*; D010447:Peptide Hydrolases / Q000172:deficiency / Q000235:genetics*; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology; D012600:Scoliosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D064448:Filamins; D009124:Muscle Proteins; C000621183:KY protein, human; D010447:Peptide Hydrolases