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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in DDHD2, encoding an intracellular phospholipase A
1
, cause a recessive form of complex hereditary spastic paraplegia
American Journal of Human Genetics, Volume 91, No. 6, Year 2012
Notification
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Description
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 A1 (iPLA1). 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 PLA1 family to human neurologic disease. © 2012 The American Society of Human Genetics.
Authors & Co-Authors
Schuurs-Hoeijmakers, Janneke H.M.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Geraghty, Michael T.
Canada, Ottawa
Children's Hospital of Eastern Ontario, Ottawa
Kamsteeg, Erik Jan
Netherlands, Nijmegen
Radboud University Medical Center
Ben-Salem, Salma
United Arab Emirates, Al Ain
United Arab Emirates University
De Bot, Susanne T.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Nijhof, Bonnie
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Van De Vondervoort, Ilse I.G.M.
Netherlands, Nijmegen
Radboud University Medical Center
van der Graaf, M.
Netherlands, Nijmegen
Radboud University Medical Center
Nobau, Anna Castells
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Otte-Höller, Irene
Netherlands, Nijmegen
Radboud University Medical Center
Vermeer, Sascha
Netherlands, Nijmegen
Radboud University Medical Center
Smith, Amanda C.
Canada, Ottawa
Ottawa Hospital Research Institute
Humphreys, Peter
Canada, Ottawa
Children's Hospital of Eastern Ontario, Ottawa
Schwartzentruber, Jeremy A.
Canada, Montreal
Université Mcgill
Ali, Bassam R.
United Arab Emirates, Al Ain
United Arab Emirates University
Al-Yahyaee, Saeed A.S.
Oman, Muscat
Sultan Qaboos University
Tariq, Said
United Arab Emirates, Al Ain
United Arab Emirates University
Pramathan, Thachillath
United Arab Emirates, Al Ain
United Arab Emirates University
Bayoumi, Riad A.L.
Oman, Muscat
Sultan Qaboos University
Kremer, Hubertus PH
Netherlands, Groningen
Universitair Medisch Centrum Groningen
van de Warrenburg, Bart P.C.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Van Den Akker, Willem M.R.
Netherlands, Nijmegen
Radboud University Medical Center
Gilissen, Christian
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Veltman, J. A.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Janssen, Irene M.
Netherlands, Nijmegen
Radboud University Medical Center
Vulto-Van Silfhout, Anneke T.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
van der Velde-Visser, Saskia D.
Netherlands, Nijmegen
Radboud University Medical Center
Lefeber, Dirk J.
Netherlands, Nijmegen
Radboud University Medical Center
Diekstra, Adinda
Netherlands, Nijmegen
Radboud University Medical Center
Erasmus, Corrie E.
Netherlands, Nijmegen
Radboud University Medical Center
Willemsen, M. A.A.P.
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Netherlands, Nijmegen
Radboud University Medical Center
Vissers, Lisenka E.L.M.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Lammens, Martin
Netherlands, Nijmegen
Radboud University Medical Center
van Bokhoven, Hans
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Brunner, Han G.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Wevers, Ron Allan
Netherlands, Nijmegen
Radboud University Medical Center
Schenck, Annette
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Al-Gazali, Lihadh I.
United Arab Emirates, Al Ain
United Arab Emirates University
De Vries, Bert B.A.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
de Brouwer, Arjan P.M.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Donders Institute for Brain, Cognition and Behaviour
Statistics
Citations: 143
Authors: 40
Affiliations: 9
Identifiers
Doi:
10.1016/j.ajhg.2012.10.017
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Disability
Genetics And Genomics