Primary familial brain calcification linked to deletion of 5’ noncoding region of <i>SLC20A2</i>

Pasanen, Petra; Mäkinen, Jussi; Myllykangas, Liisa; Guerreiro, Rita; Brás, José; Valori, Miko; Viitanen, Matti; Baumann, Marc; Tienari, Pentti J.; Pöyhönen, Minna; Baumann, Peter

doi:10.1111/ane.12697

Cited by 12 publications

(6 citation statements)

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“…Studies have shown that not only limited to coding regions, but also genetic variants in noncoding regions can affect gene action. [ 33 ]. In mammals, SNPs polymorphism in the promoter region were found to be central to the transcriptional regulatory mechanism in vitro, regulating the activity of the promoter region [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Association of Two SNPs in the Promoter Regions of the PPP2R5C and SLC39A5 Genes with Litter Size in Yunshang Black Goats

Wang

Li²,

Liu³

et al. 2022

Animals

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Screening for candidate genes and genetic variants associated with litter size is important for goat breeding. The aim of this study was to analyze the relationship between single nucleotide polymorphisms (SNPs) in PPP2R5C and SLC39A5 and litter size in Yunshang black goats. KASP genotyping was used to detect the SNP genetic markers in the PPP2R5C and SLC39A5 in a population of 569 Yunshang black goats. The results show that there were two SNPs in the PPP2R5C and SLC39A5 promoter regions. Association analysis revealed that the polymorphisms PPP2R5C g.65977743C>T and SLC39A5 g.50676693T>C were significantly associated with the litter size of the third parity of Yunshang black goats (p < 0.05). To further explore the regulatory mechanism of the two genes, the expression of different genotypes of PPP2R5C and SLC39A5 was validated by RT-qPCR and Western blotting. The expression of PPP2R5C was significantly higher in individuals with the TT genotype than in those with the TC and CC genotypes (p < 0.05). The expression of SLC39A5 was also significantly higher in individuals with the TT genotype than in TC and CC genotypes (p < 0.05). Dual luciferase reporter analysis showed that the luciferase activity of PPP2R5C-C variant was significantly higher than that of PPP2R5C-T variant (p < 0.05). The luciferase activity of SLC39A5-T variant was significantly higher than that of SLC39A5-C variant (p < 0.05). Software was used to predict the binding of transcription factors to the polymorphic sites, and the results show that SOX18, ZNF418, and ZNF667 and NKX2-4 and TBX6 might bind to PPP2R5C g.65977743C>T and SLC39A5 g.50676693T>C, respectively. These results provide new insights into the identification of candidate genes for marker-assisted selection (MAS) in goats.

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Section: Discussionmentioning

confidence: 99%

Analysis of the Association of Two SNPs in the Promoter Regions of the PPP2R5C and SLC39A5 Genes with Litter Size in Yunshang Black Goats

Wang

Li²,

Liu³

et al. 2022

Animals

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“…In carriers of pathogenic variants of SLC20A2, additional features have been reported including forms of tremor (head tremor, intention tremor of the upper limbs), blepharospasm, torticollis, facial palsy, apraxia, palilalia, myoclonus (described as mostly cortical), cramps, active denervation at electromyographic (EMG) recording, polyneuropathy, syncope, as well as ischemic episodes (both transitory and stroke) [40,41,[44][45][46][47][48][49][50][51]. Seizures have been described as both grand mal generalized or focal.…”

Section: Primary Familial Brain Calcifications: Clinical Aspectsmentioning

confidence: 99%

Brain Calcifications: Genetic, Molecular, and Clinical Aspects

Monfrini

Arienti

Rinchetti

et al. 2023

IJMS

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Many conditions can present with accumulation of calcium in the brain and manifest with a variety of neurological symptoms. Brain calcifications can be primary (idiopathic or genetic) or secondary to various pathological conditions (e.g., calcium–phosphate metabolism derangement, autoimmune disorders and infections, among others). A set of causative genes associated with primary familial brain calcification (PFBC) has now been identified, and include genes such as SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2. However, many more genes are known to be linked with complex syndromes characterized by brain calcifications and additional neurologic and systemic manifestations. Of note, many of these genes encode for proteins involved in cerebrovascular and blood–brain barrier functions, which both represent key anatomical structures related to these pathological phenomena. As a growing number of genes associated with brain calcifications is identified, pathways involved in these conditions are beginning to be understood. Our comprehensive review of the genetic, molecular, and clinical aspects of brain calcifications offers a framework for clinicians and researchers in the field.

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“…SLC20A2 gene haploinsufficiency is a likely pathogenic mechanism of brain calcification; half dosage of SLC20A2 expression cannot maintain the phosphate transport demand in the brain (Baker et al, 2014;Fujioka et al, 2015;Guo et al, 2019;Mu et al, 2019). Deletions adjacent to the regulatory element in the SLC20A2 coding region may also cause PFBC (Pasanen et al, 2017;Cassinari et al, 2020). SLC20A2 expression might be related to the severity of brain calcification to some extent, such as the genetic dosage effect observed in patients harboring MYORG mutations (Chen et al, 2019b(Chen et al, , 2020Grangeon et al, 2019).…”

Section: Slc20a2 and Pdgfb Dosage And Functional Effect In Brain Calcificationmentioning

confidence: 99%

Case Report: Two Novel Frameshift Mutations in SLC20A2 and One Novel Splice Donor Mutation in PDGFB Associated With Primary Familial Brain Calcification

et al. 2021

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Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is characterized by bilateral and symmetric brain calcification in the basal ganglia (globus pallidus, caudate nucleus, and putamen), thalamus, subcortical white matter, and cerebellum. PFBC can be caused by loss-of-function mutations in any of the six known causative genes. The most common clinical manifestations include movement disorders, cognitive impairment, and neuropsychiatric signs that gradually emerge in middle-aged patients. To broaden the PFBC mutation spectrum, we examined nine members of a family with PFBC and two sporadic cases from clinical departments, and sequenced all PFBC-causative genes in the index case. Two novel frameshift mutations in SLC20A2 [NM_001257180.2; c.806delC, p.(Pro269Glnfs*49) and c.1154delG, p.(Ser385Ilefs*70)] and one novel splice donor site mutation (NM_002608.4, c.456+1G>C, r.436_456del) in PDGFB were identified in the patient cohort. c.806delC co-segregated with brain calcification and led to SLC20A2 haploinsufficiency among the affected family members. The c.456+1G>C mutation in PDGFB resulted in aberrant mRNA splicing, thereby forming mature transcripts containing an in-frame 21 base pair (bp) deletion, which might create a stably truncated protein [p.(Val146_Gln152del)] and exert a dominant negative effect on wild-type PDGFB. All three mutations were located in highly conserved regions among multiple species and predicted to be pathogenic, as evaluated by at least eight common genetic variation scoring systems. This study identified three novel mutations in SLC20A2 and PDGFB, which broadened and enriched the PFBC mutation spectrum.

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Primary familial brain calcification linked to deletion of 5’ noncoding region of SLC20A2

Cited by 12 publications

References 38 publications

Analysis of the Association of Two SNPs in the Promoter Regions of the PPP2R5C and SLC39A5 Genes with Litter Size in Yunshang Black Goats

Analysis of the Association of Two SNPs in the Promoter Regions of the PPP2R5C and SLC39A5 Genes with Litter Size in Yunshang Black Goats

Brain Calcifications: Genetic, Molecular, and Clinical Aspects

Case Report: Two Novel Frameshift Mutations in SLC20A2 and One Novel Splice Donor Mutation in PDGFB Associated With Primary Familial Brain Calcification

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