Publication Type:

Journal Article


European Journal of Human Genetics, Volume 21, Number 11, p.1214-1218 (2013)



adult, article, cell migration, child, corpus callosum agenesis, endoplasmic reticulum, exome, family, female, gene, gene mutation, Golgi complex, hereditary motor sensory neuropathy, human, in vitro study, intracellular membrane, lipid metabolism, major clinical study, male, mental deficiency, nucleotide sequence, phenotype, phospholipase, phospholipase A1, phospholipase ddhd2, preschool child, priority journal, school child, sequence analysis, short stature, spastic paraplegia, unclassified drug


Hereditary spastic paraplegias (HSP) are a genetically heterogeneous group of disorders characterized by a distal axonopathy of the corticospinal tract motor neurons leading to progressive lower limb spasticity and weakness. Intracellular membrane trafficking, mitochondrial dysfunction and myelin formation are key functions involved in HSP pathogenesis. Only recently defects in metabolism of complex lipids have been implicated in a number of HSP subtypes. Mutations in the 23 known autosomal recessive HSP genes explain less than half of autosomal recessive HSP cases. To identify novel autosomal recessive HSP disease genes, exome sequencing was performed in 79 index cases with autosomal recessive forms of HSP. Resulting variants were filtered and intersected between families to allow identification of new disease genes. We identified two deleterious mutations in the phospholipase DDHD2 gene in two families with complicated HSP. The phenotype is characterized by early onset of spastic paraplegia, mental retardation, short stature and dysgenesis of the corpus callosum. Phospholipase DDHD2 is involved in intracellular membrane trafficking at the golgi/endoplasmic reticulum interface and has been shown to possess phospholipase A1 activity in vitro. Discovery of DDHD2 mutations in HSP might therefore provide a link between two key pathogenic themes in HSP: membrane trafficking and lipid metabolism. © 2013 Macmillan Publishers Limited.


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Cite this Research Publication

M. Gonzalez, Nampoothiri, S., Kornblum, C., Oteyza, A. C., Walter, J., Konidari, I., Hulme, W., Speziani, F., Schöls, Ld, Züchner, S., and Schüle, Rad, “Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)”, European Journal of Human Genetics, vol. 21, pp. 1214-1218, 2013.