TY - JOUR
T1 - Mutations in DDHD2, encoding an intracellular phospholipase A1, cause a recessive form of complex hereditary spastic paraplegia
AU - Schuurs-Hoeijmakers, Janneke H.M.
AU - Geraghty, Michael T.
AU - Kamsteeg, Erik Jan
AU - Ben-Salem, Salma
AU - De Bot, Susanne T.
AU - Nijhof, Bonnie
AU - Van De Vondervoort, Ilse I.G.M.
AU - Van Der Graaf, Marinette
AU - Nobau, Anna Castells
AU - Otte-Höller, Irene
AU - Vermeer, Sascha
AU - Smith, Amanda C.
AU - Humphreys, Peter
AU - Schwartzentruber, Jeremy
AU - Ali, Bassam R.
AU - Al-Yahyaee, Saeed A.
AU - Tariq, Said
AU - Pramathan, Thachillath
AU - Bayoumi, Riad
AU - Kremer, Hubertus P.H.
AU - Van De Warrenburg, Bart P.
AU - Van Den Akker, Willem M.R.
AU - Gilissen, Christian
AU - Veltman, Joris A.
AU - Janssen, Irene M.
AU - Vulto-Van Silfhout, Anneke T.
AU - Van Der Velde-Visser, Saskia
AU - Lefeber, Dirk J.
AU - Diekstra, Adinda
AU - Erasmus, Corrie E.
AU - Willemsen, Michèl A.
AU - Vissers, Lisenka E.L.M.
AU - Lammens, Martin
AU - Van Bokhoven, Hans
AU - Brunner, Han G.
AU - Wevers, Ron A.
AU - Schenck, Annette
AU - Al-Gazali, Lihadh
AU - De Vries, Bert B.A.
AU - De Brouwer, Arjan P.M.
N1 - Funding Information:
We are grateful to the studied individuals and their families for their support and cooperation. We thank Prof. N. Knoers for her contribution to the collection of the follow-up cohort and A. Heister for homozygosity analysis in family 4. This work was completed with collaboration from the FORGE Canada Consortium—supported by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research, and the Ontario Genomics Institute (OGI-049)—as well as from the Netherlands Organization for Health Research and Development (VIDI grants 917-86-319 to B.B.A.d.V. and 917-96-346 to A.S.), the GENCODYS project (EU-7 th -2010-241995 to H.v.B., A.S., A.T.V.v.S., and B.B.A.d.V.), and the Dutch Brain Foundation (2010(1)-30 to A.P.M.d.B. and 2009(1)-22 to B.B.A.d.V.). The laboratories of L.A. and B.R.A. are funded by the Dubai Harvard Foundation for Medical Research and the United Arab Emirates University.
PY - 2012/12/7
Y1 - 2012/12/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2012.10.017
DO - 10.1016/j.ajhg.2012.10.017
M3 - Article
C2 - 23176823
AN - SCOPUS:84870879483
SN - 0002-9297
VL - 91
SP - 1073
EP - 1081
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -