A Novel Missense Mutation of the DDHD1 Gene Associated with Juvenile Amyotrophic Lateral Sclerosis

Wu, Chujun

doi:10.3389/fnagi.2016.00291

Cited by 14 publications

(14 citation statements)

References 17 publications

(40 reference statements)

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“…Gene mutations are the leading cause of ALS; however, the gene mutation profiles of classical ALS and JALS are different. For instance, mutations in SOD1, TDP-43, C9ORF72, FUS, ANG, OPTN, UBQLN2 , and ATXN2 have recently been identified in classical ALS, while mutations in FUS, SIGMAR1 , SPG11, ALS2, SOD1, C19ORF12, DDHD1, SETX , and TARDBP were detected in patients with JALS (Avemaria et al, 2011 ; Daoud et al, 2012 ; Siddiqi et al, 2014 ; Wu and Fan, 2016 ; Liu et al, 2017 ; Ma et al, 2018 ; Naumann et al, 2019 ). Whereas 90% of classical ALS cases are sporadic, the proportion falls to approximately 60% for JALS (Zou et al, 2016 ; Chen et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A Human iPSC Line Carrying a de novo Pathogenic FUS Mutation Identified in a Patient With Juvenile ALS Differentiated Into Motor Neurons With Pathological Characteristics

Chen

Wang

Xie

2020

Front. Cell. Neurosci.

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Human-induced pluripotent stem cells (hiPSCs) are used to establish patient-specific cell lines and are ideal models to mirror the pathological features of diseases and investigate their underlying mechanisms in vitro , especially for rare genic diseases. Here, a de novo mutation c.1509dupA (p.R503fs) in fused in sarcoma ( FUS ) was detected in a patient with sporadic juvenile amyotrophic lateral sclerosis (JALS). JALS is a rare and severe form of ALS with unclear pathogenesis and no effective cure. An induced pluripotent stem cell (iPSC) line carrying the de novo mutation was established, and it represents a good tool to study JALS pathogenesis and gene therapy strategies for the treatment of this condition. The established human iPSC line carrying the de novo FUS mutation strongly expressed pluripotency markers and could be differentiated into three embryonic germ layers with no gross chromosomal aberrations. Furthermore, the iPSCs could be successfully differentiated into motor neurons exhibiting the pathological characteristics of ALS. Our results indicate that this line may be useful for uncovering the pathogenesis of sporadic JALS and screen for drugs to treat this disorder.

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Section: Introductionmentioning

confidence: 99%

A Human iPSC Line Carrying a de novo Pathogenic FUS Mutation Identified in a Patient With Juvenile ALS Differentiated Into Motor Neurons With Pathological Characteristics

Chen

Wang

Xie

2020

Front. Cell. Neurosci.

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“…Symptoms of SPG28 include spastic gait, hyperreflexia and mildly penetrant peripheral neuropathy, cerebellar eye movements, and urinary incontenance 9–11 . Additional neurological disorders associated with DDHD1 mutations include juvenile ALS and neurodegeneration with brain iron accumulation 12,13 . Knowledge of DDHD1-regulated lipid pathways in the CNS may thus provide insights into the mechanistic basis for SPG28 and point to future treatment strategies for the disease.…”

Section: Introductionmentioning

confidence: 99%

The Spastic Paraplegia-Associated Phospholipase DDHD1 Is a Primary Brain Phosphatidylinositol Lipase

2018

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Deleterious mutations in the serine hydrolase DDHD domain containing 1 (DDHD1) cause the SPG28 subtype of the neurological disease hereditary spastic paraplegia (HSP), which is characterized by axonal neuropathy and gait impairments. DDHD1 has been shown to display PLA1-type phospholipase activity with a preference for phosphatidic acid. However, the endogenous lipid pathways regulated by DDHD1 in vivo remain poorly understood. Here we use a combination of untargeted and targeted metabolomics to compare the lipid content of brain tissue from DDHD1 and DDHD1 mice, revealing that DDHD1 inactivation causes a substantial decrease in the level of polyunsaturated lysophosphatidylinositol (LPI) lipids and a corresponding increase in the level of phosphatidylinositol (PI) lipids. Levels of other phospholipids were mostly unchanged, with the exception of decreases in the levels of select polyunsaturated lysophosphatidylserine (LPS) and lysophosphatidylcholine lipids and a striking remodeling of PI phosphates (e.g., PIP and PIP2) in DDHD1 brain tissue. Biochemical assays confirmed that DDHD1 hydrolyzes PI/PS to LPI/LPS with sn-1 selectivity and accounts for a substantial fraction of the PI/PS lipase activity in mouse brain tissue. These data indicate that DDHD1 is a principal regulator of bioactive LPI and other lysophospholipids, as well as PI phosphates, in the mammalian nervous system, pointing to a potential role for these lipid pathways in HSP.

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“…DDHD domain containing 1 ( DDHD1 ) is associated with one case report of JALS [ 77 ]. DDHD1 is an intracellular phospholipase involved in the regulation of mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Juvenile Amyotrophic Lateral Sclerosis: A Review

Lehky

2021

Genes

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Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases. JALS is defined as onset before age 25. We conducted a literature review of JALS and gene mutations associated with JALS. Results of the literature review show that the most common gene mutations associated with JALS are FUS, SETX, and ALS2. In familial cases, the gene mutations are mostly inherited in an autosomal recessive pattern and mutations in SETX are inherited in an autosomal dominant fashion. Disease prognosis varies from rapidly progressive to an indolent course. Distinct clinical features may emerge with specific gene mutations in addition to the clinical finding of combined upper and lower motor neuron degeneration. In conclusion, patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations. Hereditary patterns and coexisting features may be useful in determining prognosis.

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A Novel Missense Mutation of the DDHD1 Gene Associated with Juvenile Amyotrophic Lateral Sclerosis

Cited by 14 publications

References 17 publications

A Human iPSC Line Carrying a de novo Pathogenic FUS Mutation Identified in a Patient With Juvenile ALS Differentiated Into Motor Neurons With Pathological Characteristics

A Human iPSC Line Carrying a de novo Pathogenic FUS Mutation Identified in a Patient With Juvenile ALS Differentiated Into Motor Neurons With Pathological Characteristics

The Spastic Paraplegia-Associated Phospholipase DDHD1 Is a Primary Brain Phosphatidylinositol Lipase

Juvenile Amyotrophic Lateral Sclerosis: A Review

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