Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 (spastin).
The authors report a nucleotide substitution (c.1216A>G) in SPG4 (spastin) causing hereditary spastic paraplegia. This apparent missense mutation in the ATPase domain confers aberrant, in-frame splicing and results in destabilization of mutated transcript. Mutated protein is deficient in microtubule-severing activity but, unlike neighboring mutations, shows regular subcellular localization. The authors' data point to haploinsufficiency rather than a dominant negative effect as the disease-causing mechanism for this mutation.
Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum, Friedrich-Schiller Universität, Jena, Germany.
J
J
Schickel
C
C
Beetz
C
C
Frömmel
G
G
Heide
A
A
Sasse
P
P
Hemmerich
T
T
Deufel
D000225:Adenine; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D004252:DNA Mutational Analysis; D005684:Gait; D005799:Genes, Dominant; D006147:Guanine; D006801:Humans; D007866:Leg; D008297:Male; D008870:Microtubules; D009129:Muscle Tonus; D018908:Muscle Weakness; D020125:Mutation, Missense; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology*; D000074181:Spastin; D014162:Transfection
D006147:Guanine; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human; D000225:Adenine