A de novo <i>MAPRE2</i> variant in a patient with congenital symmetric circumferential skin creases type 2

Feng, Jincai; Lan, Xiaoping; Shen, Jun; Song, Xiaozhen; Tang, Xiaojun; Xu, Wenteng; Ren, Xiang; Zhang, Hong; Yu, Guangjun; Wu, Shengnan

doi:10.1002/mgg3.1096

Cited by 7 publications

(6 citation statements)

References 14 publications

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“…Sequencing data were analyzed to identify sequence variants [single nucleotide variant (SNV), insertion/deletion (Ins/Del)] and copy number variants (CNVs) using an in-house pipeline (Fulgent genetics). A phenotype-driven gene list was created to perform a primary variant interpretation for a more targeted analysis ( 4 ). After data analysis, variant filtering, and prioritization, a novel compound heterozygote mutation, c.3596G> A (p.C1199Y)/ex.9del (p.216-248del) in NBAS was identified ( Figure 1A ).…”

Section: Case Presentationmentioning

confidence: 99%

Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations

Jiang

Xiao

et al. 2021

Front. Pediatr.

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Acute liver failure (ALF) in childhood is a rapidly progressive, potentially life-threatening condition that occurs in previously healthy children of all ages. However, the etiology of ~50% of cases with pediatric ALF remains unknown. We herein report a 4-year-old Chinese girl with recurrent ALF (RALF) due to a mutation in the neuroblastoma amplified sequence (NBAS) gene. The patient had suffered from multiple episodes of fever-related ALF since early childhood. She had also suffered from acute kidney injury, hypertension, mild pulmonary hypertension, pleural effusion, and hypothyroidism. A novel compound heterozygote mutation, c.3596G> A (p.C1199Y)/ex.9del (p.216-248del), in the NBAS gene was identified by whole-exome sequencing (WES). The missense mutation c.3596G> A (p. C1199Y) was inherited from her father, and ex.9del (p.216-248del) was inherited from her mother. The patient was managed with intensive treatments, such as renal replacement therapy (CRRT), intravenous antibiotics, and glucose infusion, and was discharged after full recovery. We identified a novel compound heterozygote mutation in the NBAS gene that caused fever-related RALF in a Chinese child, which further expands the mutational spectrum of NBAS.

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Section: Case Presentationmentioning

confidence: 99%

Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations

Jiang

Xiao

et al. 2021

Front. Pediatr.

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“…Eleven cases of CSC‐KT were confirmed by gene sequencing from 2015 to 2020 (Dentici et al, 2018; Feng et al, 2020; Isrie et al, 2015; Li et al, 2020; Niu et al, 2020) including six cases of the TUBB and five cases of the MAPRE2 variants. Previous studies have shown that two patients with homozygous pathogenic variants in MAPRE2 had severe neurological dysfunction, accompanied by intellectual impairment and seizures, whereas there was no neurological dysfunction in the patients with pathogenic TUBB variants.…”

Section: Discussionmentioning

confidence: 99%

Diaphragmatic paralysis in a neonate with circumferential skin creases Kunze type

Fang

Kaiwei

Lingkong

et al. 2022

Molec Gen & Gen Med

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Circumferential skin creases-Kunze type (CSC-KT) is a rare autosomal-dominant inherited disease associated with pathogenic variants of TUBULIN BETA (TUBB; OMIM: #191130) and MICROTUBULE-ASSOCIATED PROTEIN, RP/EB FAMILY, MEMBER 2 (MAPRE2; OMIM: #605789) (Tinsa et al., 2009;Wouters et al., 2011). The typical clinical manifestations are skin creases on limbs, also known as Michelin Tire baby syndrome (Ross, 1969). Wouters et al. (2011) coined the term "CSC-KT," specifically referring to children with multiple malformations such as cleft palate, facial deformity, growth retardation, genital malformation, and intellectual disability (Kunze & Riehm, 1982;Wouters et al., 2011) in addition to CSC.TUBB and MAPRE2 gene mutations are associated with CSC-KT, which are consistent with the genetic heterogeneity of the disease (Isrie et al., 2015). The clinical phenotype was reported prior to the widespread clinical application of gene sequencing technology. A published limited cohort study found that TUBB and MAPRE2 genes were associated with the genotype-phenotype profile of CSC-KT (Breuss et al., 2012). The authors reported three missense mutations and one nonsense mutation in the calci-protein homology domain of the MAPRE2 gene and three missense mutations in the TUBB gene (Goldspink et al., 2013).

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confidence: 99%

“…16 Interestingly, human mutations in MAPRE2 have been implicated in congenital symmetrical circumferential skin creases type 2, although the genetic and molecular mechanisms are not well defined and the cardiac phenotype has not yet been characterized. 17,18 To understand the role of EB2 in cardiac arrhythmia, we used the zebrafish model, which exhibits cardiac electrophysiology similar to that of humans. 19 Previously, we knocked out mapre2 acutely in F0 zebrafish using a multi-gRNA CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) approach 20 and observed a ventricular phenotype consistent with…”

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The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction

Chiang,

Verkerk,

Victorio

et al. 2024

Circulation Research

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BACKGROUND: The Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2 , which encodes EB (microtubule end-binding protein) 2, implicating microtubule involvement in the Brugada syndrome. METHODS: A mapre2 knockout zebra fish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebra fish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human iPSC-derived cardiomyocytes with MAPRE2 knockdown and knockout, respectively. RESULTS: Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC cardiomyocytes. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC cardiomyocytes led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. CONCLUSIONS: Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel–related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.

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A de novo MAPRE2 variant in a patient with congenital symmetric circumferential skin creases type 2

Cited by 7 publications

References 14 publications

Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations

Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations

Diaphragmatic paralysis in a neonate with circumferential skin creases Kunze type

The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction

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