Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

Vaz, Frédéric M.; McDermott, John H; Alders, Mariëlle; Wortmann, Saskia B.; Kölker, Stefan; Pras‐Raves, Mia L.; Vervaart, Martin A. T.; Lenthe, Henk van; Luyf, Angela C. M.; Elfrink, Hyung L.; Metcalfe, Kay; Cuvertino, Sara; Clayton, Peter E.; Yarwood, Rebecca; Lowe, Martin; Lovell, Simon C.; Rogers, R. Curtis; Study, Deciphering Developmental Disorders; Kampen, Antoine H. C. van; Ruiter, J. P. N.; Wanders, Ronald J. A.; Ferdinandusse, Sacha; Weeghel, Michel van; Engelen, Marc; Banka, Siddharth

doi:10.1093/brain/awz291

Cited by 84 publications

(100 citation statements)

References 40 publications

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“…To date, more than 82 known or suspected genes or genetic loci have been reported to cause HSP. 4 Notably, it has been proposed that many autosomal recessive HSP genes remain unidentified. 3 Recently, loss-of-function mutations in the CAPN1 gene have been described as causative for spastic paraplegia 76 (SPG76).…”

Section: Introductionmentioning

confidence: 99%

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

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Objective: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity. Methods: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases. Results: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs*103, c.759+1G>A, and p.R285*), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015). Interpretation: Our study supports the clinically heterogeneous inter-and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

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Section: Introductionmentioning

confidence: 99%

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

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“…Very recently, Vaz et al generated two distinct pcyt2 knockout zebrafish lines, one targeting exon 3 (pcyt2_03) and the other targeting the final exon 13 (pcyt2_13) (Vaz et al, 2019). The gene PCYT2 encodes phosphoethanolamine cytidylyltransferase, an enzyme in the phosphatidylethanolamine synthesis via, one of the most abundant membrane lipids presents in the brain (Nakashima et al, 1997).…”

Section: Pcyt2mentioning

confidence: 99%

“…Moreover, at 6 weeks of age, the pcyt2_13 line showed smaller size and abnormal tailfin morphology compared with the WT. This model highlighted that alterations in lipid metabolism may lead to complex HSP (Martin et al, 2013;Vaz et al, 2019).…”

Section: Pcyt2mentioning

confidence: 99%

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

et al. 2019

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Hereditary spastic paraplegia (HSP) and hereditary ataxia (HA) are two groups of disorders characterized, respectively, by progressive dysfunction or degeneration of the pyramidal tracts (HSP) and of the Purkinje cells and spinocerebellar tracts (HA). Although HSP and HA are generally shown to have distinct clinical-genetic profiles, in several cases the clinical presentation, the causative genes, and the cellular pathways and mechanisms involved overlap between the two forms. Genetic analyses in humans in combination with in vitro and in vivo studies using model systems have greatly expanded our knowledge of spinocerebellar degenerative disorders. In this review, we focus on the zebrafish (Danio rerio), a vertebrate model widely used in biomedical research since its overall nervous system organization is similar to that of humans. A critical analysis of the literature suggests that zebrafish could serve as a powerful experimental tool for molecular and genetic dissection of both HA and HSP. The zebrafish, found to be very useful for demonstrating the causal relationship between defect and mutation, also offers a useful platform to exploit for the development of therapies.

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“…PE plays important roles in membrane fusion, the regulation of cholesterol homeostasis, mitochondria function, and autophagy [ 3 – 6 ]. Thus, maintaining PE homeostasis is critical for neurons to survive and function [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a hypomorphic mutation in PCYT2 (a component of the CDP-ethanolamine pathway) was shown to cause recessive forms of progressive neurodegeneration, namely spastic paraplegia disorders [ 7 ]. Homozygous mutations in PSD genes cause a range of conditions, including skeletal dysplasia, early-onset retinal degeneration, hearing loss, microcephaly, and intellectual disability [ 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila

Zhao

Wang

2020

PLoS Genet

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The major glycerophospholipid phosphatidylethanolamine (PE) in the nervous system is essential for neural development and function. There are two major PE synthesis pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the phosphatidylserine decarboxylase (PSD) pathway in mitochondria. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown. Here, we show that Drosophila pect (phosphoethanolamine cytidylyltransferase) mutants lacking the CDP-ethanolamine pathway, exhibited alterations in phospholipid composition, defective phototransduction, and retinal degeneration. Induction of the PSD pathway fully restored levels and composition of cellular PE, thus rescued the retinal degeneration and defective visual responses in pect mutants. Disrupting lipid exchange between mitochondria and ER blocked the ability of PSD to rescue pect mutant phenotypes. These findings provide direct evidence that the synthesis of PE in mitochondria contributes to cellular PE homeostasis, and suggest the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency.

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Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

Cited by 84 publications

References 40 publications

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila

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