Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

Michael Gonzalez, Sheela Nampoothiri, Cornelia Kornblum, Andrés Caballero Oteyza, Jochen Walter, Ioanna Konidari, William Hulme, Fiorella Speziani, Ludger Schöls, Stephan Züchner, Rebecca Schüle

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1214-1218
Number of pages5
JournalEuropean Journal of Human Genetics
Volume21
Issue number11
DOIs
StatePublished - Nov 1 2013

Keywords

  • exome sequencing
  • Hereditary spastic paraplegia
  • neurodegenerative disease

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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    Gonzalez, M., Nampoothiri, S., Kornblum, C., Oteyza, A. C., Walter, J., Konidari, I., Hulme, W., Speziani, F., Schöls, L., Züchner, S., & Schüle, R. (2013). Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). European Journal of Human Genetics, 21(11), 1214-1218. https://doi.org/10.1038/ejhg.2013.29