MYORG Mutations: a Major Cause of Recessive Primary Familial Brain Calcification

Bauer, M; Rahat, Dolev; Zisman, Elad; Tabach, Yuval; Lossos, Alexander; Meiner, Vardiella; Arkadir, David

doi:10.1007/s11910-019-0986-z

Cited by 15 publications

(9 citation statements)

References 31 publications

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“…Our previous study suggests that mutations of MYORG are the main cause of autosomal recessive PFBC (Yao et al, 2018). To date, more than 50 variants associated with PFBC have been reported in different ethnic populations, further confirming the pathogenicity of MYORG mutations (Bauer et al, 2019;Westenberger et al, 2019). In this study, we identified four novel variants of MYORG including two missense variants and two nonsense variants in four sporadic cases.…”

Section: Discussionsupporting

confidence: 70%

Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

Zeng

Lin

et al. 2021

Front. Genet.

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Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C > T, c.972C > A), one likely pathogenic variant (c.2033C > G), and one variant of uncertain significance (c.1969G>C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.

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Section: Discussionsupporting

confidence: 70%

Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

Zeng

Lin

et al. 2021

Front. Genet.

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“…The Fmod protein regulates the expression of atrophy-related genes to alleviate muscle atrophy by regulating the TGF signaling pathway 25 , 26 . In contrast, myogenesis regulating glycosidase (MYORG) is a glycosidase that has an important role in myoblast differentiation and is involved in movement disorders and cognitive impairment 27 , 28 . On the other hand, PGS2 (decorin) is important for maintenance of glucose tolerance, and PGS2 knockout decreased glucose tolerance 29 .…”

Section: Resultsmentioning

confidence: 99%

Defect in cytosolic Neu2 sialidase abrogates lipid metabolism and impairs muscle function in vivo

Son

et al. 2022

Sci Rep

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Sialic acid (SA) is present in glycoconjugates and important in cell–cell recognition, cell adhesion, and cell growth and as a receptor. Among the four mammalian sialidases, cytosolic NEU2 has a pivotal role in muscle and neuronal differentiation in vitro. However, its biological functions in vivo remain unclear due to its very low expression in humans. However, the presence of cytoplasmic glycoproteins, gangliosides, and lectins involved in cellular metabolism and glycan recognition has suggested the functional importance of cytosolic Neu2 sialidases. We generated a Neu2 knockout mouse model via CRISPR/Cas9-mediated genome engineering and analyzed the offspring littermates at different ages to investigate the in vivo function of cytosolic Neu2 sialidase. Surprisingly, knocking out the Neu2 gene in vivo abrogated overall lipid metabolism, impairing motor function and leading to diabetes. Consistent with these results, Neu2 knockout led to alterations in sialylated glycoproteins involved in lipid metabolism and muscle function, as shown by glycoproteomics analysis.

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“…Co-evolution across the tree of life can predict proteins that are associated with the same function, share common pathways, and contribute to corresponding diseases ( Tabach et al., 2013a , 2013b ; Omar et al., 2018 ; Arkadir et al., 2019 ; Bauer et al., 2019 ; Sherill-Rofe et al., 2019 ). To map the proteins that co-evolved with ACE2, we generated an extensive database of 1,671 eukaryotic proteomes and identified the set of genes that showed similar phylogenetic profiles to ACE2 ( Figures 2 A and S3 ).…”

Section: Resultsmentioning

confidence: 99%

ACE2 Co-evolutionary Pattern Suggests Targets for Pharmaceutical Intervention in the COVID-19 Pandemic

Braun¹,

Sharon²,

Unterman³

et al. 2020

iScience

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Summary The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spillover infection in December 2019 has caused an unprecedented pandemic. SARS-CoV-2, as other coronaviruses, binds its target cells through the angiotensin-converting enzyme 2 (ACE2) receptor. Accordingly, this makes ACE2 research essential for understanding the zoonotic nature of coronaviruses and identifying novel drugs. Here we present a systematic analysis of the ACE2 conservation and co-evolution protein network across 1,671 eukaryotes, revealing an unexpected conservation pattern in specific metazoans, plants, fungi, and protists. We identified the co-evolved protein network and pinpointed a list of drugs that target this network by using data integration from different sources. Our computational analysis found widely used drugs such as nonsteroidal anti-inflammatory drugs and vasodilators. These drugs are expected to perturb the ACE2 network affecting infectivity as well as the pathophysiology of the disease.

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MYORG Mutations: a Major Cause of Recessive Primary Familial Brain Calcification

Cited by 15 publications

References 31 publications

Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

Defect in cytosolic Neu2 sialidase abrogates lipid metabolism and impairs muscle function in vivo

ACE2 Co-evolutionary Pattern Suggests Targets for Pharmaceutical Intervention in the COVID-19 Pandemic

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