Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates

Sphingolipidoses are monogenic lipid storage diseases caused by variants in enzymes of lipid synthesis and metabolism. We describe an autosomal recessive complex neurological disorder affecting consanguineous kindred. All four affected individuals, born at term following normal pregnancies, had mild to severe intellectual disability, spastic quadriplegia, scoliosis and epilepsy in most, with no dysmorphic features. Brain MRI findings were suggestive of leukodystrophy, with abnormal hyperintense signal in the periventricular perioccipital region and thinning of the body of corpus callosum. Notably, all affected individuals were asymptomatic at early infancy and developed normally until the age of 8-18 months, when deterioration ensued. Homozygosity mapping identified a single 8.7 Mb disease-associated locus on chromosome 1q41-1q42.13 between rs1511695 and rs537250 (two-point LOD score 2.1). Whole exome sequencing, validated through Sanger sequencing, identified within this locus a single disease-associated homozygous variant in DEGS1, encoding C4-dihydroceramide desaturase, an enzyme of the ceramide synthesis pathway. The missense variant, segregating within the family as expected for recessive heredity, affects an evolutionary-conserved amino acid of all isoforms of DEGS1 (c.656A>G, c.764A>G; p.(N219S), p.(N255S)) and was not found in a homozygous state in ExAC and gnomAD databases or in 300 ethnically matched individuals. Lipidomcs analysis of whole blood of affected individuals demonstrated augmented levels of dihydroceramides, dihydrosphingosine, dihydrosphingosine-1-phosphate and dihydrosphingomyelins with reduced levels of ceramide, sphingosine, sphingosine-1-phosphate and monohexosylceramides, as expected in malfunction of C4-dihydroceramide desaturase. Thus, we describe a sphingolipidosis causing a severe regressive neurological disease.

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“…Analysis was done as previously described [7]. In brief: UPLC-Q-TOF-MS/MS analysis of sphingolipids.…”

Section: Simultaneous Quantitative Analysis Of Bioactive Sphingolipidmentioning

confidence: 99%

DEGS1 variant causes neurological disorder

Dolgin

Straussberg

et al. 2019

Eur J Hum Genet

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“…Next, we uncover that TIM regulates S1P biosynthesis by controlling the expression of ACER2. Previous research has demonstrated that ACER2 plays a vital role in the maintenance of S1P in plasma by controlling the production of sphingosine (SPH) in hematopoietic cells 22 . Several researches indicate that ACER2 is associated with proliferation, apoptosis, DNA damage response, and autophagy in diverse cancer cells [33][34][35][36][37] .…”

Section: Discussionmentioning

confidence: 99%

TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer

et al. 2020

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Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Here, we explored that the expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with specificity protein 1 (Sp1) which contributes to upregulate the expression of alkaline ceramidase 2 (ACER2). Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Collectively, our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer.

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“…Elevated levels of ceramide are known to be correlated with adverse cardiac events, whereas SPH has been shown to increase intracellular NO levels and maintain the mitochondrial integrity of the cardiovascular system [ 33 ]. Conversely, increased blood S1P levels are associated with the pathogenesis of inflammatory and cardiovascular diseases [ 85 ]. Hence, an association between ceramidase and cardiopulmonary events is expected.…”

Section: Role Of Ceramidase Activity In Human Non-heritable Diseasmentioning

confidence: 99%

“…However, an overexpression of ACER2 has been associated with chronic obstructive pulmonary disease (COPD) [ 89 ]. ACER2 inhibition contributes to a reduction in the circulating S1P and its analogue, dhS1P, as well as their precursors, SPH and dhSPH, in hematopoietic cells and reduces the concentration of dhS1P in the lungs [ 85 , 88 ].…”

Section: Role Of Ceramidase Activity In Human Non-heritable Diseasmentioning

confidence: 99%

Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration

Duarte

Akkaoui

Yamada

et al. 2020

Cells

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Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3—have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer’s disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed.

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Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates

Cited by 30 publications

References 45 publications

DEGS1 variant causes neurological disorder

DEGS1 variant causes neurological disorder

TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer

Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration

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