Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis.
OBJECTIVE
Recessive mutations in ALS2 (juvenile amyotrophic lateral sclerosis) are causative for early-onset upper motor neuron diseases, including infantile ascending hereditary spastic paralysis (IAHSP). The goal of this study is to identify novel disease-causing ALS2 mutations.


METHODS
Mutations in ALS2 were screened by direct sequencing of complementary DNA obtained from patients' lymphoblasts.


RESULTS
We report a novel ALS2 missense mutation in patients affected by IAHSP. This homozygous G669A mutation in exon 4 is predicted to result in a tyrosine substitution at cysteine 156 of the RCC1 (regulator of chromatin condensation)-like domain, encoding a putative guanine exchange factor for Ran guanosine triphosphatase, leading to a loss of ALS2 function due to instability of mutant protein.


CONCLUSIONS
These results highlight the important role of the RCC1-like domain in ALS2 stability and function that is essential for upper motor neuron maintenance.
Eymard-Pierre
Eleonore
E
Institut National de la Sante et de la Recherche Médicale U384 and Human Genetics Department, CHU, Clermont-Ferrand, France.
Yamanaka
Koji
K
Haeussler
Martin
M
Kress
Wolfram
W
Gauthier-Barichard
Fernande
F
Combes
Patricia
P
Cleveland
Don W
DW
Boespflug-Tanguy
Odile
O
D000328:Adult; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D012689:Sequence Homology, Nucleic Acid; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
C438187:ALS2 protein, human; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C062521:RCC1 protein, human