title: HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.
abstract: OBJECTIVE
  To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies.
  
  
  METHODS
  Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization.
  
  
  RESULTS
  We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population.
  
  
  CONCLUSIONS
  Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies.
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany. Burkhard.Gess@ukmuenster.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Gess
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schirmacher
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strom
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zitzelsberger
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Röhr
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Halfter
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: From the Department of Sleep Medicine and Neuromuscular Disorders (B.G., A.S., D.R., H.H., P.Y.), University of Muenster, Germany; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; Institute of Human Genetics (T.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Friedrich Baur Institute (M.Z., J.S.), Department of Neurology, Ludwig Maximilians University Munich; and Institute of Human Genetics (S.R.-S.), RWTH Aachen University, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
mesh_terms: D000200:Action Potentials / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001317:Austria; D018797:Cell Cycle Proteins / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004576:Electromyography; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005858:Germany; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; C470309:MAD2L1BP protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins