title: Milder forms of muscular dystrophy associated with POMGNT2 mutations.
abstract: OBJECTIVE
  To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants.
  
  
  METHODS
  A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins.
  
  
  RESULTS
  WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells.
  
  
  CONCLUSIONS
  Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens.
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Mingrui
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuru
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Nagai
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ozasa
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino