Loss of Function of Glucocerebrosidase GBA2 Is Responsible for Motor Neuron Defects in Hereditary Spastic Paraplegia

摘要: Spastic paraplegia 46 refers to a locus mapped chromosome 9 that accounts for complicated autosomal-recessive form of hereditary spastic (HSP). With next-generation sequencing in three independent families, we identified four different mutations GBA2 (three truncating variants and one missense variant), which were found cosegregate with the disease absent controls. encodes microsomal nonlysosomal glucosylceramidase catalyzes conversion glucosylceramide free glucose ceramide hydrolysis bile acid 3-O-glucosides. The variant was also at homozygous state simplex subject whom no residual glucocerebrosidase activity could be evidenced blood cells, opening way possible measurement this enzyme clinical practice. overall phenotype complex HSP mental impairment, cataract, hypogonadism males associated various degrees corpus callosum cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting zebrafish orthologous gene led abnormal motor behavior axonal shortening/branching motoneurons rescued by human wild-type mRNA but not applying same containing mutation. This study highlights role metabolism pathology.