Lack of Major Ophthalmic Findings in Patients with Primary Familial Brain Calcification Linked to SLC20A2 and PDGFB

Borges-Medeiros, Rayssa L.; Ferreira, Laura Durão; Oliveira, João Ricardo Mendes de

doi:10.1007/s12031-018-1250-8

Cited by 5 publications

(2 citation statements)

References 23 publications

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“…Interestingly, microphthalmia and cataracts were reported in Slc20a2 −/− mice [ 33 ], however, whether these mice present with abnormalities in retinal vasculature has not been reported. No ophthalmic findings were found in SLC20A2 and PDGFB mutation carriers [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis

Maheshwari,

Mateos,

Weber‐Stadlbauer

et al. 2023

Brain Pathology

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Calcification of the cerebral microvessels in the basal ganglia in the absence of systemic calcium and phosphate imbalance is a hallmark of primary familial brain calcification (PFBC), a rare neurodegenerative disorder. Mutation in genes encoding for sodium‐dependent phosphate transporter 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), platelet‐derived growth factor B (PDGFB), platelet‐derived growth factor receptor beta (PDGFRB), myogenesis regulating glycosidase (MYORG), and junctional adhesion molecule 2 (JAM2) are known to cause PFBC. Loss‐of‐function mutations in XPR1, the only known inorganic phosphate exporter in metazoans, causing dominantly inherited PFBC was first reported in 2015 but until now no studies in the brain have addressed whether loss of one functional allele leads to pathological alterations in mice, a commonly used organism to model human diseases. Here we show that mice heterozygous for Xpr1 (Xpr1WT/lacZ) present with reduced inorganic phosphate levels in the cerebrospinal fluid and age‐ and sex‐dependent growth of vascular calcifications in the thalamus. Vascular calcifications are surrounded by vascular basement membrane and are located at arterioles in the smooth muscle layer. Similar to previously characterized PFBC mouse models, vascular calcifications in Xpr1WT/lacZ mice contain bone matrix proteins and are surrounded by reactive astrocytes and microglia. However, microglial activation is not confined to calcified vessels but shows a widespread presence. In addition to vascular calcifications, we observed vessel tortuosity and transmission electron microscopy analysis revealed microangiopathy—endothelial swelling, phenotypic alterations in vascular smooth muscle cells, and thickening of the basement membrane.

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Section: Discussionmentioning

confidence: 99%

Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis

Maheshwari,

Mateos,

Weber‐Stadlbauer

et al. 2023

Brain Pathology

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“…Slc20a2 encodes a type III sodium-dependent PIT-2 and acts as a gatekeeper in regulating Pi uptake and maintaining brain Pi homeostasis (Inden et al, 2016;Wallingford et al, 2017). Slc20a2-HO mice, with 19% relative Slc20a2 gene expression, exhibited some unique overall appearances, such as developmental delay, skeleton malformation, cataract, or microphthalmia (Wallingford et al, 2016(Wallingford et al, , 2017Jensen et al, 2018;Beck-Cormier et al, 2019), which were not observed in patients with heterozygous SLC20A2, even barely in those harboring compound heterozygous or homozygous SLC20A2 mutations (Wang et al, 2012;de Oliveira et al, 2013;Borges-Medeiros et al, 2019;Chen et al, 2019). Elevated Pi levels and severe calcification in the hypothalamus might induce neuroendocrine cell dysfunction, leading to hormonal deficiencies and growth delay in PFBC mice (Wu et al, 2018).…”

Section: Gene Dosage Effect and Sensitivity In Mice And Patients With Pfbcmentioning

confidence: 99%

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Ren

Shen

et al. 2021

Front. Genet.

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BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

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Overlapping Diseases in a Brazilian Subject with Brain Calcification Linked to Novel Phenotypes

Ferreira

Oliveira

2020

J Mol Neurosci

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Lack of Major Ophthalmic Findings in Patients with Primary Familial Brain Calcification Linked to SLC20A2 and PDGFB

Cited by 5 publications

References 23 publications

Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis

Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Overlapping Diseases in a Brazilian Subject with Brain Calcification Linked to Novel Phenotypes

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