Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome

Bardhan, Mainak; Polavarapu, Kiran; Bevinahalli, Nandeesh; Preethish‐Kumar, Veeramani; Anjanappa, Ram Murthy; Arunachal, Gautham; Shingavi, Leena; Vengalil, Seena; Nashi, Saraswati; Chawla, Tanushree; Nagabushana, Divya; Mohan, Dhaarini; Horvath, Rita; Nishino, Ichizo; Nalini, Atchayaram

doi:10.1038/s10038-021-00913-1

Cited by 8 publications

(7 citation statements)

References 17 publications

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“…Based on these findings, MAGEF1 might related with ICPs via m6A modification or CIA pathways, which needed to be further explored. CHKB (choline kinase beta) played a key role maintaining the normal phosphatidylcholine level ( 50 ). The relationship between CHKB and glioma haven’t been explored.…”

Section: Discussionmentioning

confidence: 99%

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses

et al. 2022

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PurposeGlioblastoma multiforme (GBM) is a common and aggressive form of brain tumor. The N6-methyladenosine (m6A) mRNA modification plays multiple roles in many biological processes and disease states. However, the relationship between m6A modifications and the tumor microenvironment in GBM remains unclear, especially at the single-cell level.Experimental DesignSingle-cell and bulk RNA-sequencing data were acquired from the GEO and TCGA databases, respectively. We used bioinformatics and statistical tools to analyze associations between m6A regulators and multiple factors.ResultsHNRNPA2B1 and HNRNPC were extensively expressed in the GBM microenvironment. m6A regulators promoted the stemness state in GBM cancer cells. Immune-related BP terms were enriched in modules of m6A-related genes. Cell communication analysis identified genes in the GALECTIN signaling network in GBM samples, and expression of these genes (LGALS9, CD44, CD45, and HAVCR2) correlated with that of m6A regulators. Validation experiments revealed that MDK in MK signaling network promoted migration and immunosuppressive polarization of macrophage. Expression of m6A regulators correlated with ICPs in GBM cancer cells, M2 macrophages and T/NK cells. Bulk RNA-seq analysis identified two expression patterns (low m6A/high ICP and high m6A/low ICP) with different predicted immune infiltration and responses to ICP inhibitors. A predictive nomogram model to distinguish these 2 clusters was constructed and validated with excellent performance.ConclusionAt the single-cell level, m6A modification facilitates the stemness state in GBM cancer cells and promotes an immunosuppressive microenvironment through ICPs and the GALECTIN signaling pathway network. And we also identified two m6A-ICP expression patterns. These findings could lead to novel treatment strategies for GBM patients.

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Section: Discussionmentioning

confidence: 99%

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses

et al. 2022

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“…Megaconial CMD is an autosomal recessive disorder, nearly 40 patients of which have been identified in the literature to date, with the majority being of Turkish origin [Haliloglu et al, 2015]. The most common manifestations are neonatal/infantile-onset hypotonia, progressive generalized muscle weakness, autistic behavior, intellectual disability, ichthyosis-like skin manifestations, and cardiomyopathy [Kutluk et al, 2020;Bardhan et al, 2021]. Most patients have mildly elevated serum CK levels [Kutluk et al, 2020], while rare manifestations include seizures, severe mental retardation, hearing loss, dysmorphic facial features (long facial appearance, upwardcurved palpebral space, hypertelorism, flattening above the eye, deep sunken eyes, nasal bridge, low-set ears, wide and protruding lower lip, low hairline) and microcephaly [Haliloglu et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

Coexistence of Megaconial Congenital Muscular Dystrophy and Cystinuria: Mimicking Hypotonia-Cystinuria Syndrome

et al. 2022

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Introduction: Hypotonia-cystinuria syndrome is a contiguous gene deletion syndrome that is characterized by hypotonia, developmental delay, and cystinuria type A. We present a male patient who was admitted to our center with clinical findings of hypotonia-cystinuria syndrome and diagnosed with megaconial congenital muscular dystrophy and cystinuria. Case Presentation: A 16-month-old male patient was admitted with complaints of restlessness and body laxity. It was stated that the patient had hypotonia and growth retardation at the age of 2 months. Physical examination revealed mild hypotonia, growth retardation, and development delay, while laboratory examinations identified elevated serum creatine kinase and elevated dibasic amino acid in urine analysis. Because of the findings of hypotonia, growth retardation, developmental delay, and cystinuria, hypotonia-cystinuria syndrome was considered as a differential diagnosis. However, by chromosomal microarray no contiguous deletion in region 2p21 was found, while a novel homozygous c.225-2A>T pathogenic variant in the CHKB gene and a c.1266_1267delGT heterozygous variant in the SLC7A9 gene inherited from the mother were identified with whole-exome sequencing. The co-occurrence of megaconial congenital muscular dystrophy and cystinuria, mimicking hypotonia-cystinuria syndrome, was confirmed. Conclusion: This case suggests that in countries with a high frequency of consanguineous marriage, even if the molecular genetic analysis results are not compatible with the clinical findings, it should be kept in mind that different genetic diseases may coexist.

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“…Severity of DD/ID ranges between mild to severe and recently, pathogenic variants in CHKB have been associated with autism spectrum disorder and atypical Rett syndrome. 5,20 The abnormalities on muscle biopsy include muscular dystrophy as well as mitochondrial enlargement and placement in the periphery of muscle fibers. The muscular biopsy of individual 4 in this study also showed mitochondrial abnormalities with dense matrix and regular cristae, but mitochondria were evenly distributed throughout the cell.…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

Kloeckner

Murray

Tavasoli

et al. 2021

Preprint

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The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI).We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway.In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

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Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome

Cited by 8 publications

References 17 publications

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses

Coexistence of Megaconial Congenital Muscular Dystrophy and Cystinuria: Mimicking Hypotonia-Cystinuria Syndrome

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

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