Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.
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.
Dierick
Ines
I
Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
Baets
Jonathan
J
Irobi
Joy
J
Jacobs
An
A
De Vriendt
Els
E
Deconinck
Tine
T
Merlini
Luciano
L
Van den Bergh
Peter
P
Rasic
Vedrana Milic
VM
Robberecht
Wim
W
Fischer
Dirk
D
Morales
Raul Juntas
RJ
Mitrovic
Zoran
Z
Seeman
Pavel
P
Mazanec
Radim
R
Kochanski
Andrzej
A
Jordanova
Albena
A
Auer-Grumbach
Michaela
M
Helderman-van den Enden
A T J M
AT
Wokke
John H J
JH
Nelis
Eva
E
De Jonghe
Peter
P
Timmerman
Vincent
V
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
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