scholarly journals Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Fatemeh Bitarafan ◽  
Mehrnoosh Khodaeian ◽  
Elham Amjadi Sardehaei ◽  
Fatemeh Zahra Darvishi ◽  
Navid Almadani ◽  
...  

Abstract Background Ca2+ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation, and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1), which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca2+ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene causes a very rare neuromuscular disease, myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca2+ uptake. To date, 13 variants have been reported in MICU1 gene in 44 patients presented with the vast spectrum of symptoms. Case presentation Here, we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH). We identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing (WES) and segregation analysis. Conclusions Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.

2020 ◽  
Author(s):  
Fatemeh Bitarafan ◽  
Mehrnoosh Khodaeian ◽  
Elham Amjadi Sardehaei ◽  
Fatemeh Zahra Darvishi ◽  
Navid Almadani ◽  
...  

Abstract Background: Ca2+ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1) which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca2+ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene (NM_006077.3) causes a very rare neuromuscular disease, Myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca2+ uptake. To date 6 variants have been reported in MICU1 gene in approximately 21 pedigrees.Case presentation: here we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, elevated hepatic transaminase, elevated serum creatine phosphokinase and gait disturbance. We Identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing and segregation analysis.Conclusions: Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.


Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Hannah E. Henson ◽  
Michael R. Taylor

The spliceosome consists of accessory proteins and small nuclear ribonucleoproteins (snRNPs) that remove introns from RNA. As splicing defects are associated with degenerative conditions, a better understanding of spliceosome formation and function is essential. We provide insight into the role of a spliceosome protein U4/U6.U5 tri-snRNP-associated protein 1, or Squamous cell carcinoma antigen recognized by T-cells (Sart1). Sart1 recruits the U4.U6/U5 tri-snRNP complex to nuclear RNA. The complex then associates with U1 and U2 snRNPs to form the spliceosome. A forward genetic screen identifying defects in choroid plexus development and whole-exome sequencing (WES) identified a point mutation in exon 12 of sart1 in Danio rerio (zebrafish). This mutation caused an up-regulation of sart1. Using RNA-Seq analysis, we identified additional upregulated genes, including those involved in apoptosis. We also observed increased activated caspase 3 in the brain and eye and down-regulation of vision-related genes. Although splicing occurs in numerous cells types, sart1 expression in zebrafish was restricted to the brain. By identifying sart1 expression in the brain and cell death within the central nervous system (CNS), we provide additional insights into the role of sart1 in specific tissues. We also characterized sart1’s involvement in cell death and vision-related pathways.


Cell Calcium ◽  
2006 ◽  
Vol 40 (5-6) ◽  
pp. 553-560 ◽  
Author(s):  
György Hajnóczky ◽  
György Csordás ◽  
Sudipto Das ◽  
Cecilia Garcia-Perez ◽  
Masao Saotome ◽  
...  

Author(s):  
Afsaneh BAZGIR ◽  
Mehdi AGHA GHOLIZADEH ◽  
Faezeh SARVAR ◽  
Zahra PAKZAD

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly )ASPM( gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.


1964 ◽  
Vol 12 (02) ◽  
pp. 471-483 ◽  
Author(s):  
F Rodríguez-Erdmann

SummaryThe rôle of the clotting system in the pathogenesis of the generalized Shwartzman reaction (gSr) has been stressed in recent years. The clotting system is activated ubiquitously and as a result of it, fibrin is deposited intravascularly and a haemorrhagic diathesis develops. Evidence is presented herein, that endotoxin does not activate purified prothrombin, nor does endotoxin influence the convertion of prothrombin when it is activated in the presence of purified platelet-factor 3 (or caephalin) purified Ac-G (factor V) and Ca-ions.The trigger mechanism of the gSr also seems to be in the so-called prephase of clotting mechanism. Data are presented, which show that endotoxin activates the Hageman factor in vitro. The importance of this clotting factor and of platelet-factor 3 is discussed. Also the rôle played by the RES and cardiodynamic and vascular components are taken in consideration in the discussion.


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