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. 2013 Nov;21(11):1214-8.
doi: 10.1038/ejhg.2013.29. Epub 2013 Mar 13.

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

Michael Gonzalez  1 , Sheela Nampoothiri, Cornelia Kornblum, Andrés Caballero Oteyza, Jochen Walter, Ioanna Konidari, William Hulme, Fiorella Speziani, Ludger Schöls, Stephan Züchner, Rebecca Schüle
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Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54)

Michael Gonzalez et al. Eur J Hum Genet. 2013 Nov.

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.

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Figures

Figure 1
Figure 1
Pedigrees and mutations. (a) Pedigrees and sequence traces of the DDHD2 families. The c.859C>T mutation segregates in family THI26003 and leads to the formation of a preterminal stop signal at codon 287. The c.1982_1983delAT mutation segregates in family IHG25194; it results in a frameshift at amino acid position 661. (b) Schematic of the DDHD2 gene. The DDHD2 gene contains three known protein domains. The WWE domain is predicted to mediate protein interactions in ubiquitin and ADP ribose conjugation systems. The tandem SAM (sterile alpha motif domain) – DDHD domain is required for phosphoinositide binding. Integrity of the family-defining DDHD domain, present in DDHD2 as well as its homolog DDHD1, is necessary for the PLA1 catalytic activity and homo-oligomerization of DDHD2. Catalytic function as well as a positively charged cluster in the SAM domain (Arg434-Lys435-Lys436) also required for phosphoinositide binding are necessary to promote membrane localization., Mutations previously described are indicated in black, novel mutations in red.
Figure 2
Figure 2
Cranial MRI/CT scans of DDHD2 patients. MRI/CT scans of DDHD2 patients show dysgenesis of the corpus callosum as well as some paucity of the periventricular white matter (d). (a): coronal MRI (T1 inversion recovery) of THI26003-4. (b): axial CT-scan of THI26003-3. (c): sagittal MRI (T1) of IHG25194-3. (d): axial MRI (T1) of IHG25194-3.
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