title: Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.
abstract: Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.
authors.affiliation: Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors.forename: Ines
authors.initials: I
authors.lastname: Dierick
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: An
authors.initials: A
authors.lastname: Jacobs
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Peter
authors.initials: P
authors.lastname: Van den Bergh
authors.forename: Vedrana Milic
authors.initials: VM
authors.lastname: Rasic
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
authors.forename: Raul Juntas
authors.initials: RJ
authors.lastname: Morales
authors.forename: Zoran
authors.initials: Z
authors.lastname: Mitrovic
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kochanski
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: A T J M
authors.initials: AT
authors.lastname: Helderman-van den Enden
authors.forename: John H J
authors.initials: JH
authors.lastname: Wokke
authors.forename: Eva
authors.initials: E
authors.lastname: Nelis
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004265:DNA Helicases; D004594:Electrophysiology; D005260:Female; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics; D005838:Genotype; D055551:HSP27 Heat-Shock Proteins; D006239:Haplotypes; D006360:Heat-Shock Proteins / Q000235:genetics; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D009030:Mosaicism; D064251:Multifunctional Enzymes; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020365:RNA Helicases / Q000235:genetics
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D064251:Multifunctional Enzymes; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases