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 L Zuchner, Rebecca Schüle

Research output: Contribution to journalArticle

36 Citations (Scopus)

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

Fingerprint

Hereditary Spastic Paraplegia
Phospholipases
Mutation
Intracellular Membranes
Lipid Metabolism
Genes
Phospholipases A1
Agenesis of Corpus Callosum
Exome
Pyramidal Tracts
Paraplegia
Motor Neurons
Membrane Lipids
Myelin Sheath
Intellectual Disability
Endoplasmic Reticulum
Lower Extremity

Keywords

  • exome sequencing
  • Hereditary spastic paraplegia
  • neurodegenerative disease

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Gonzalez, M., Nampoothiri, S., Kornblum, C., Oteyza, A. C., Walter, J., Konidari, I., ... 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

Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). / Gonzalez, Michael; Nampoothiri, Sheela; Kornblum, Cornelia; Oteyza, Andrés Caballero; Walter, Jochen; Konidari, Ioanna; Hulme, William; Speziani, Fiorella; Schöls, Ludger; Zuchner, Stephan L; Schüle, Rebecca.

In: European Journal of Human Genetics, Vol. 21, No. 11, 01.11.2013, p. 1214-1218.

Research output: Contribution to journalArticle

Gonzalez, M, Nampoothiri, S, Kornblum, C, Oteyza, AC, Walter, J, Konidari, I, Hulme, W, Speziani, F, Schöls, L, Zuchner, SL & Schüle, R 2013, 'Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)', European Journal of Human Genetics, vol. 21, no. 11, pp. 1214-1218. https://doi.org/10.1038/ejhg.2013.29
Gonzalez M, Nampoothiri S, Kornblum C, Oteyza AC, Walter J, Konidari I et al. Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). European Journal of Human Genetics. 2013 Nov 1;21(11):1214-1218. https://doi.org/10.1038/ejhg.2013.29
Gonzalez, Michael ; Nampoothiri, Sheela ; Kornblum, Cornelia ; Oteyza, Andrés Caballero ; Walter, Jochen ; Konidari, Ioanna ; Hulme, William ; Speziani, Fiorella ; Schöls, Ludger ; Zuchner, Stephan L ; Schüle, Rebecca. / Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). In: European Journal of Human Genetics. 2013 ; Vol. 21, No. 11. pp. 1214-1218.
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