Osteopetrosis infantil maligna

Vomero, Alejandra; Tapié, Alejandra; Arroyo, Concepción Herrera; Raggio, Víctor; Peluffo, Gabriel; Dufort, Gustavo

doi:10.32641/rchped.v90i4.987

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…In this condition, osteoclasts fail to resorb bone and clinical symptoms include osteosclerosis, thrombocytopenia, anemia, hepatosplenomegaly, and in some cases, visual impairment ( Kornak et al, 2000 ). Alteration to normal bone resorption and remodeling results in an abundance of osteoid, which reduces bone marrow space, a region where hematopoiesis occurs, leading to the gradual reduction of blood production ( Vomero et al, 2019 ). In severe cases, patients show neurological complications, including cranial neuropathies, due to progressive compression of the cranial nerves, spinal cords, and blood vessels ( Steward, 2003 ).…”

Section: Diseases Related To Non-neural Subunit a Isoformsmentioning

confidence: 99%

“…Additionally, mutations on the splice donor site, such as a T-to-C transition on intron 19, a common region to OC116 and TIRC7 , potentially resulted in abnormal splicing of both transcripts ( Michigami et al, 2002 ). Therefore, MIOP patients commonly presented immune anomalies and a high incidence of infections ( Vomero et al, 2019 ). Some other reported variants in the ATP6V0A3 are compound heterozygous mutations of E266GfsX12 with E463G ( Vomero et al, 2019 ), E399RTer with E112R in a milder version of the disease ( Luong et al, 2022 ), G172D, V285Afs*204, and c.C324Wfs*X166 ( Figure 5B ; Liu et al, 2021 ).…”

Section: Diseases Related To Non-neural Subunit a Isoformsmentioning

confidence: 99%

“…Therefore, MIOP patients commonly presented immune anomalies and a high incidence of infections ( Vomero et al, 2019 ). Some other reported variants in the ATP6V0A3 are compound heterozygous mutations of E266GfsX12 with E463G ( Vomero et al, 2019 ), E399RTer with E112R in a milder version of the disease ( Luong et al, 2022 ), G172D, V285Afs*204, and c.C324Wfs*X166 ( Figure 5B ; Liu et al, 2021 ).…”

Section: Diseases Related To Non-neural Subunit a Isoformsmentioning

confidence: 99%

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Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms

Indrawinata,

Argiropoulos,

Sugita

2023

Front. Mol. Neurosci.

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The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translocation upon ATP hydrolysis, mediated by the cytosolic V1 complex. Four known subunit a isoforms (a1–a4) are expressed in different cellular locations. Subunit a1 (also known as Voa1), the neural isoform, is strongly expressed in neurons and is encoded by the ATP6V0A1 gene. Global knockout of this gene in mice causes embryonic lethality, whereas pyramidal neuron-specific knockout resulted in neuronal cell death with impaired spatial and learning memory. Recently reported, de novo and biallelic mutations of the human ATP6V0A1 impair autophagic and lysosomal activities, contributing to neuronal cell death in developmental and epileptic encephalopathies (DEE) and early onset progressive myoclonus epilepsy (PME). The de novo heterozygous R740Q mutation is the most recurrent variant reported in cases of DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues in subunit c, highlighting its importance to the overall V-ATPase function. In this paper, we discuss the structure and mechanism of the V-ATPase, emphasizing how mutations in subunit a1 can lead to lysosomal and autophagic dysfunction in neurodevelopmental disorders, and how mutations to the non-neural isoforms, a2–a4, can also lead to various genetic diseases. Given the growing discovery of disease-causing variants of V-ATPase subunit a and its function as a pump-based regulator of intracellular organelle pH, this multiprotein complex warrants further investigation.

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Section: Diseases Related To Non-neural Subunit a Isoformsmentioning

confidence: 99%

Section: Diseases Related To Non-neural Subunit a Isoformsmentioning

confidence: 99%

Section: Diseases Related To Non-neural Subunit a Isoformsmentioning

confidence: 99%

See 1 more Smart Citation

Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms

Indrawinata,

Argiropoulos,

Sugita

2023

Front. Mol. Neurosci.

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Malignant infantile osteopetrosis in 3-year-old Yemeni child: a case report

Thabet¹,

Almajeedi²,

Mohammed³

et al. 2022

Pan Afr Med J

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Infantile malignant osteopetrosis (IMOP) is a rare bone resorptive disorder with an autosomal recessive inheritance pattern. It is characterized by increased bone density due to osteoclastic failure in differentiation or function. The clinical manifestations of IMOP start at birth or infancy with varied rings according to the type and degree of osteopetrosis. We presented a 3-year-old female patient referred to us due to chronic anaemia six months ago. The physical examination revealed hepatosplenomegaly, axial hypotonia, and visual impairment. Blood investigation revealed pancytopenia and hypocalcemia. Radiologic studies revealed a generalized increase in bone density, abnormal metaphyseal remodelling, and rain atrophy. The bone marrow aspiration (BMA) shows dry tap and hypocellularity of all cell lines. IMOP was diagnosed depending on clinical, radiologic, and BMA results. In conclusion, IMOP is relatively uncommon. Accurate diagnosis should be made through clinical, BMA, and radiologic investigations, especially in a resource-limited setting, as performed in our case.

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BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1

et al. 2022

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Background Dysregulated osteoclast activity due to altered osteoclast differentiation causes multiple bone diseases. Osteoclasts are multinucleated giant cells derived from hematopoietic stem cells and play a major role in bone absorption. However, the mechanisms underlying the tight regulation of osteoclast differentiation in multiple pathophysiological status remain unknown. Results We showed that Bhlhe40 upregulation is tightly associated with osteoclast differentiation and osteoporosis. Functionally, Bhlhe40 promoted osteoclast differentiation in vitro, and Bhlhe40 deficiency led to increased bone mass and decreased osteoclast differentiation in vivo. Moreover, Bhlhe40 deficient mice resisted estrogen deficiency and aging-induced osteoporosis. Mechanism study showed that the increase in bone mass due to Bhlhe40 deficiency was a cell intrinsic defect in osteoclast differentiation in these mice. BHLHE40 upregulated the gene expression of Fos and Nfatc1 by directly binding to their promoter regions. Notably, inhibition of Fos/Nfatc1 abrogated the enhanced osteoclast differentiation induced by BHLHE40 overexpression. Conclusions Our research reveals a novel Bhlhe40/c-Fos/Nfatc1 axis involved in regulating osteoclastogenesis and shows that osteoporosis caused by estrogen deficiency and aging can be rescued by regulating Bhlhe40 in mice. This may help in the development of a new strategy for the treatment of osteoporosis.

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Osteopetrosis infantil maligna

Cited by 4 publications

References 7 publications

Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms

Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms

Malignant infantile osteopetrosis in 3-year-old Yemeni child: a case report

BHLHE40 promotes osteoclastogenesis and abnormal bone resorption via c-Fos/NFATc1

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