scholarly journals Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

2021 ◽  
Vol 11 (3) ◽  
pp. 122-128
Author(s):  
Priya Bhardwaj ◽  
Christoffer Rasmus Vissing ◽  
Niels Kjær Stampe ◽  
Kasper Rossing ◽  
Alex Hørby Christensen ◽  
...  

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

2021 ◽  
Vol 10 (16) ◽  
pp. 3471
Author(s):  
Lidia Carreño-Gago ◽  
Diana Luz Juárez-Flores ◽  
Josep Maria Grau ◽  
Javier Ramón ◽  
Ester Lozano ◽  
...  

Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson’s syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson’s syndrome characteristics and MLASA related phenotypes.


Author(s):  
P Hutsteiner ◽  
N Jenewein ◽  
J Christ ◽  
O Ortmann ◽  
U Germer

Circulation ◽  
1995 ◽  
Vol 92 (12) ◽  
pp. 3387-3389 ◽  
Author(s):  
Jean-Bernard Durand ◽  
Linda L. Bachinski ◽  
Lisa C. Bieling ◽  
Grazyna Z. Czernuszewicz ◽  
Antoine B. Abchee ◽  
...  

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 674
Author(s):  
Francesco Capriglia ◽  
Francesca Rizzo ◽  
Giuseppe Petrosillo ◽  
Veronica Morea ◽  
Giulia d’Amati ◽  
...  

The m.3243A>G mutation within the mitochondrial mt-tRNALeu(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samina Yasin ◽  
Outi Makitie ◽  
Sadaf Naz

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.


2011 ◽  
Vol 108 (8) ◽  
pp. 1171-1176 ◽  
Author(s):  
Mario Petretta ◽  
Flora Pirozzi ◽  
Laura Sasso ◽  
Antonella Paglia ◽  
Domenico Bonaduce

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