<scp><i>VPS4A</i></scp> mutation in syndromic congenital hemolytic anemia without obvious signs of dyserythropoiesis

Lunati, Ariane; Petit, Arnaud; Lapillonne, Hélène; Gameiro, Christine; Saillour, Virginie; Garel, Catherine; Doummar, Diane; Qebibo, Leila; Aissat, Abdelrazak; Fanen, Pascale; Bartolucci, Pablo; Galactéros, F; Funalot, Benoît; Bürglen, Lydie; Mansour‐Hendili, Lamisse

doi:10.1002/ajh.26099

Cited by 3 publications

(5 citation statements)

References 10 publications

(30 reference statements)

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“…In addition to driving MVB biogenesis for receptor downregulation, the ESCRTs facilitate abscission during cytokinesis, the biogenesis of extracellular vesicles and many viruses, closure of the autophagosome, repairing plasma membrane lesions, and maintaining nuclear envelope integrity. The critical contributions of ESCRTs to mammalian physiology is highlighted by the embryonic lethality of mouse ESCRT knockout models [9][10][11] and the disease-associated mutations linked to ESCRT genes [13][14][15][16][17][18][19][20][21][22][23][24][25]. For example, the PTPN23 (HD-PTP) mouse knockout model is embryonic lethal [12], and mutations in HD-PTP/PTPN23 are linked to NEDBASS [26][27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with roles in diverse, important cellular processes, disrupted ESCRT function through knockout of ESCRT-0 (hrs) [9], ESCRT-I (tsg101) [10], ESCRT-III (chmp5) [11] or the ESCRT-associated factor HD-PTP (ptpn23) [12] result in embryonic lethality in mouse models. Moreover, mutations altering ESCRT function have been linked to congenital disorders including spastic paraplegia (SP80, UBAP1; SP53, Vps37A) [13][14][15], childhood cataracts (CTRCT31, CHMP4B) [16,17], frontotemporal dementia (FTD/ALS17, CHMP2B) [18][19][20][21], pontocerebellar hypoplasia (PCH8, CHMP1A) [22], cerebellar hypoplasia, cataracts, impaired intellectual development, congenital microcephaly, dystonia, dyserythropoietic anemia, and growth retardation (CIMDAG, VPS4A) [23][24][25] and neurodevelopmental disorder with structural brain anomalies, seizures and spasticity (NEDBASS, HDPTP/PTPN23) [26][27][28][29][30] (also reviewed in [31]). While the ESCRTs serve important roles facilitating development and maintaining organismal homeostasis, the lack of a viable ESCRT-deficient mouse model has precluded a deeper understanding of how this is achieved.…”

Section: Introductionmentioning

confidence: 99%

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HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

Davies¹,

Payne²,

Martin³

et al. 2022

Preprint

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Endosomal Sorting Complexes Required for Transport (ESCRTs) drive reverse topology membrane remodeling events including the formation of intralumenal vesicles within multivesicular bodies, the budding of retroviruses from the plasma membrane, and the scission of the cytokinetic bridge. It has been difficult to study the physiological relevance of this machinery in mammals because many contributing components are essential for viability. To bypass this problem we used combinations of knockout (−), hypomorphic (H) and wildtype (+) alleles to generate a series of mice with a gradual reduction of HD-PTP (product of PTPN23), an ESCRT-associated protein known to cause embryonic lethality when fully depleted. Whereas PTPN23−/H mice died shortly after birth, PTPN23H/H mice developed into adulthood but had reduced size, lipodystrophy, and shortened lifespan. Analysis of 14-day inguinal adipose tissue indicated reduced expression of adipogenesis markers, and PTPN23 knockout preadipocytes similarly display reduced adipogenesis in vitro. Defects in insulin-stimulated signaling were apparent in differentiated PTPN23 knockout adipocytes and PTPN23H/H inguinal adipose tissue in vitro, correlating with reduced levels of insulin signaling hallmarks observed in adult PTPN23H/H inguinal adipose tissue in vivo. Whereas the ESCRT machinery have been suggested to downregulate signaling, these results indicate that HD-PTP promotes insulin-induced signaling in, as well as differentiation of, inguinal adipose tissue. These results revealed unexpected roles for HD-PTP in promoting fat accumulation in mammalian cells through supporting insulin signaling, adipogenesis, and lipid droplet formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

Davies¹,

Payne²,

Martin³

et al. 2022

Preprint

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“…More recently, an additional patient with a severe neurodevelopmental disorder resulting from VPS4A mutation (p.Arg284Trp) has been reported [132]. This patient had severe transfusion-dependent anemia with brisk reticulocytosis but no evidence of dyserythropoiesis on bone marrow evaluation [132]. Notably, subtle dyserythropoitic findings can be seen in disorders of hereditary chronic hemolytic anemias, such as pyruvate kinase deficiency [121] and hereditary xerocytosis [121,135].…”

Section: Other Congenital Dyserythropoietic Anemiasmentioning

confidence: 99%

Section: Other Congenital Dyserythropoietic Anemiasmentioning

confidence: 99%

The congenital dyserythropoieitic anemias: genetics and pathophysiology

King

Gallagher

Khoriaty

2021

Current Opinion in Hematology

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Purpose of reviewThe congenital dyserythropoietic anemias (CDA) are hereditary disorders characterized by ineffective erythropoiesis. This review evaluates newly developed CDA disease models, the latest advances in understanding the pathogenesis of the CDAs, and recently identified CDA genes.Recent findingsMice exhibiting features of CDAI were recently generated, demonstrating that Codanin-1 (encoded by Cdan1) is essential for primitive erythropoiesis. Additionally, Codanin-1 was found to physically interact with CDIN1, suggesting that mutations in CDAN1 and CDIN1 result in CDAI via a common mechanism. Recent advances in CDAII (which results from SEC23B mutations) have also been made. SEC23B was found to functionally overlap with its paralogous protein, SEC23A, likely explaining the absence of CDAII in SEC23B-deficient mice. In contrast, mice with erythroid-specific deletion of 3 or 4 of the Sec23 alleles exhibited features of CDAII. Increased SEC23A expression rescued the CDAII erythroid defect, suggesting a novel therapeutic strategy for the disease. Additional recent advances included the identification of new CDA genes, RACGAP1 and VPS4A, in CDAIII and a syndromic CDA type, respectively.SummaryEstablishing cellular and animal models of CDA is expected to result in improved understanding of the pathogenesis of these disorders, which may ultimately lead to the development of new therapies.

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“…Symptoms arising from problems with muscle tone such as hypotonia and dystonia are also thought to be central in nature (Ganguly et al, 2021). In addition, mutations in VPS4A are associated with Congenital Dyserythropoietic Anemia (Seu et al, 2020; Lunati et al, 2021). VPS4A encodes a type I AAA-ATPase that was originally identified in yeast.…”

Section: Introductionmentioning

confidence: 99%

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants

Shipman,

Gao,

Liu

et al. 2024

Preprint

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Mutations in humanVPS4Aare associated with neurodevelopmental defects, including motor delays and defective muscle tone.VPS4Aencodes a AAA-ATPase that is required for membrane scission, but how mutations inVPS4Alead to impaired control of motor function is not known. Here we identified a mutation in zebrafishvps4a, T248I, that affects sensorimotor transformation. In biochemical experiments we show that the T248I mutation reduces the ATPase activity of Vps4a and disassembly of its substrate, ESCRT filaments, which mediate membrane scission. Consistent with the established role for Vps4a in the endocytic pathway and exosome biogenesis,vps4aT248Imutants have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes. Resembling the central form of hypotonia in humanVPS4Apatients, motor neurons and muscle cells are unaffected in mutant zebrafish as they react robustly to touch. Unlike somatosensory function, optomotor responses, vestibulospinal (VS), and acoustic startle reflexes are severely impaired invps4aT248Imutants, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings indicate that visual ability is largely reduced in the mutants, however,in vivoimaging of tone-evoked responses in the inner ear and ascending auditory pathway show comparable activity. Further investigation of central pathways invps4aT248Imutants revealed that sensory cues failed to fully activate neurons in the VS and medial longitudinal fasciculus (MLF) nuclei that directly innervate motor neurons. Our results suggest that a defect in sensorimotor transformation underlies the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a.

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VPS4A mutation in syndromic congenital hemolytic anemia without obvious signs of dyserythropoiesis

Cited by 3 publications

References 10 publications

HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

The congenital dyserythropoieitic anemias: genetics and pathophysiology

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants

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