title: Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54).
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.
authors.affiliation: Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kornblum
authors.forename: Andrés Caballero
authors.initials: AC
authors.lastname: Oteyza
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.forename: Ioanna
authors.initials: I
authors.lastname: Konidari
authors.forename: William
authors.initials: W
authors.lastname: Hulme
authors.forename: Fiorella
authors.initials: F
authors.lastname: Speziani
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010740:Phospholipases / Q000235:genetics*; D015203:Reproducibility of Results; D015419:Spastic Paraplegia, Hereditary / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics*; D014057:Tomography, X-Ray Computed
chemical_list: D010740:Phospholipases; C541017:DDHD2 protein, human