Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome.
OBJECTIVE
Distal hereditary motor neuropathy type V (dHMN-V) and Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand involvement, also known as CMT2D and Silver syndrome (SS) are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are considered candidates for dHMN-V, CMT2, and SS.


METHODS
To define the frequency and distribution of mutations in the GARS, BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial patients diagnosed as either dHMN-V, CMT2D or SS. Exon 3 of the BSCL2 gene was screened in further 69 individuals with an unclassified dHMN phenotype or diagnosed as hereditary spastic paraplegia (HSP) complicated by pure motor neuropathy.


RESULTS
Four patients diagnosed with dHMN-V or SS carried known heterozygous BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations and 3% for GARS mutations. In the series of unclassified dHMN and complicated HSP cases no mutations were found.


CONCLUSIONS
Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1 and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore suggest that a genetic testing of dHMN-V and SS patients should begin with screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in patients with CMT2 with predominant hand involvement and dHMN-V. The rather low frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS patients strongly point to further genetic heterogeneity of these related disorders.
Institute of Human Genetics, Medical University Graz, Austria.
Barbara
B
Rohkamm
Mary M
MM
Reilly
Hanns
H
Lochmüller
Beate
B
Schlotter-Weigel
Nina
N
Barisic
Ludger
L
Schöls
Garth
G
Nicholson
Davide
D
Pareyson
Matilde
M
Laurà
Andreas R
AR
Janecke
Gabriel
G
Miltenberger-Miltenyi
Elisabeth
E
John
Carina
C
Fischer
Franz
F
Grill
William
W
Wakeling
Mary
M
Davis
Thomas R
TR
Pieber
Michaela
M
Auer-Grumbach
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics*; D018740:Genetic Heterogeneity; D055551:HSP27 Heat-Shock Proteins; D006225:Hand / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000235:genetics; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000150:complications / Q000235:genetics; D013577:Syndrome
D048868:Adaptor Proteins, Signal Transducing; C432679:BSCL2 protein, human; D018797:Cell Cycle Proteins; D044388:GTP-Binding Protein gamma Subunits; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; C470309:MAD2L1BP protein, human; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases