Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.

Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.

American journal of human genetics (2012-11-28)

Janneke H M Schuurs-Hoeijmakers, Michael T Geraghty, Erik-Jan Kamsteeg, Salma Ben-Salem, Susanne T de Bot, Bonnie Nijhof, Ilse I G M van de Vondervoort, Marinette van der Graaf, Anna Castells Nobau, Irene Otte-Höller, Sascha Vermeer, Amanda C Smith, Peter Humphreys, Jeremy Schwartzentruber, Bassam R Ali, Saeed A Al-Yahyaee, Said Tariq, Thachillath Pramathan, Riad Bayoumi, Hubertus P H Kremer, Bart P van de Warrenburg, Willem M R van den Akker, Christian Gilissen, Joris A Veltman, Irene M Janssen, Anneke T Vulto-van Silfhout, Saskia van der Velde-Visser, Dirk J Lefeber, Adinda Diekstra, Corrie E Erasmus, Michèl A Willemsen, Lisenka E L M Vissers, Martin Lammens, Hans van Bokhoven, Han G Brunner, Ron A Wevers, Annette Schenck, Lihadh Al-Gazali, Bert B A de Vries, Arjan P M de Brouwer

PMID23176823

摘要

We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease.