Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways

2013 ◽  
Vol 450 (2) ◽  
pp. 345-350 ◽  
Author(s):  
Laura van Berge ◽  
Josta Kevenaar ◽  
Emiel Polder ◽  
Agnès Gaudry ◽  
Catherine Florentz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Enzyme Activity ◽  
Catalytic Activity ◽  
White Matter ◽  
Autosomal Recessive ◽  
Trna Synthetase ◽  
Compound Heterozygous ◽  
Small Contribution ◽  
Missense Mutations ◽  
White Matter Disorder

The autosomal recessive white matter disorder LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is caused by mutations in DARS2, coding for mtAspRS (mitochondrial aspartyl-tRNA synthetase). Generally, patients are compound heterozygous for mutations in DARS2. Many different mutations have been identified in patients, including several missense mutations. In the present study, we have examined the effects of missense mutations found in LBSL patients on the expression, enzyme activity, localization and dimerization of mtAspRS, which is important for understanding the cellular defect underlying the pathogenesis of the disease. Nine different missense mutations were analysed and were shown to have various effects on mtAspRS properties. Several mutations have a direct effect on the catalytic activity of the enzyme; others have an effect on protein expression or dimerization. Most mutations have a clear impact on at least one of the properties of mtAspRS studied, probably resulting in a small contribution of the missense variants to the mitochondrial aspartylation activity in the cell.

scholarly journals Leucoencephalopathy with brain stem and spinal cord involvement and lactate elevation: a novel mutation in the DARS2 gene

2019 ◽  
Vol 12 (1) ◽  
pp. bcr-2018-227755 ◽  
Author(s):  
Anudeep Yelam ◽  
Elanagan Nagarajan ◽  
Miguel Chuquilin ◽  
Raghav Govindarajan
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Brain Stem ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Trna Synthetase ◽  
Dorsal Column ◽  
Clinical Findings ◽  
Cerebral White Matter ◽  
Spinal Cord Involvement

Leucoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a very rare autosomal recessive, slowly progressive neurological disorder characterised by distinctive clinical findings including cerebellar, pyramidal and dorsal column dysfunction. This is caused by a mutation in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase. MRI shows distinctive abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. Here, we present a case of LBSL, with a novel c.1192-2A>G mutation.

scholarly journals A New DARS2 Mutation Discovered in an Adult Patient

2020 ◽  
Vol 12 (1) ◽  
pp. 107-113
Author(s):  
Rosy N’Gbo N’Gbo Ikazabo ◽  
Christian Mostosi ◽  
Patrice Jissendi ◽  
Marie-Anne Labaisse ◽  
Isabelle Vandernoot
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Adult Patient ◽  
Pathogenic Mutation ◽  
Trna Synthetase ◽  
Compound Heterozygous ◽  
Synthetase Activity ◽  
Compound Heterozygosity ◽  
Resonance Imaging ◽  
Brain And Spinal Cord

We report a case of an adult patient suffering from leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate (LBSL) caused by a DARS2 polymorphism. DARS2 mutation was identified by combining MRI and genetic analysis. Our patient was affected by compound heterozygosity for a pathogenic mutation and a common variant, but with reduced aspartyl-tRNA synthetase activity. Brain and spinal cord magnetic resonance imaging revealed extensive white matter abnormalities; spectroscopy revealed no lactate elevation. A new compound heterozygous DARS2 variant combined with a polymorphism in the other allele in an adult patient with LBSL was identified, resulting in reduced DARS2 activity. This combination is rare and has consequences on how we should consider benign variant polymorphisms in the future.

scholarly journals Novel Missense Mutations in BEST1 Are Associated with Bestrophinopathies in Lebanese Patients

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 151 ◽  
Author(s):  
Lama Jaffal ◽  
Wissam Joumaa ◽  
Alexandre Assi ◽  
Charles Helou ◽  
Christel Condroyer ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Subretinal Fluid ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Autosomal Recessive Bestrophinopathy ◽  
Homozygous Mutations ◽  
Flanking Regions ◽  
Reduced Light ◽  
Exon 10

To identify Bestrophin 1 (BEST1) causative mutations in six Lebanese patients from three families, of whom four had a presumed clinical diagnosis of autosomal recessive bestrophinopathy (ARB) and two showed a phenotype with a single vitelliform lesion, patients were subjected to standard ophthalmic examinations. In addition, BEST1 exons and their flanking regions were amplified and sequenced by Sanger sequencing. Co-segregation and detailed bio-informatic analyses were performed. Clinical examination results were consistent with ARB diagnosis for all index patients showing multifocal vitelliform lesions and a markedly reduced light peak in the electrooculogram, including the two patients with a single vitelliform lesion. In all cases, most likely disease-causing BEST1 mutations co-segregated with the phenotype. The ARB cases showed homozygous missense variants (M1, c.209A>G, p.(Asp70Gly) in exon 3, M2, c.1403C>T; p.(Pro468Leu) in exon 10 and M3, c.830C>T, p.(Thr277Met) in exon 7), while the two patients with a single vitelliform lesion were compound heterozygous for M1 and M2. To our knowledge, this is the first study describing mutations in Lebanese patients with bestrophinopathy, where novel biallelic BEST1 mutations associated with two phenotypes were identified. Homozygous mutations were associated with multifocal lesions, subretinal fluid, and intraretinal cysts, whereas compound heterozygous ones were responsible for a single macular vitelliform lesion.

scholarly journals LBSL

2021 ◽  
Vol 7 (2) ◽  
pp. e559 ◽  
Author(s):  
Menno D. Stellingwerff ◽  
Sonia Figuccia ◽  
Emanuele Bellacchio ◽  
Karin Alvarez ◽  
Claudia Castiglioni ◽  
...  
Keyword(s):  
White Matter ◽  
Mitochondrial Function ◽  
Trna Synthetase ◽  
Null Alleles ◽  
Compound Heterozygous ◽  
White Matter Abnormalities ◽  
Missense Variants ◽  
Tract Involvement ◽  
Group 2 ◽  
Group 1

ObjectiveLeukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes.MethodsWe reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function.ResultsWe found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5′-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function.ConclusionsDARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

scholarly journals Chinese families with autosomal recessive hereditary spastic paraplegia caused by mutations in SPG11

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xueping Chen ◽  
Jiao Liu ◽  
Qian-Qian Wei ◽  
Ru Wei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Recessive ◽  
The Other ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Spastic Paraplegia ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
Lateral Sclerosis

Abstract Background Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population. Methods Targeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing. Results A total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration. Conclusions The results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.

scholarly journals Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

2019 ◽  
Vol 5 (2) ◽  
pp. e565 ◽  
Author(s):  
Chong Sun ◽  
Jie Song ◽  
Yanjun Jiang ◽  
Chongbo Zhao ◽  
Jiahong Lu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Protein Function ◽  
Trna Synthetase ◽  
Insertion Mutation ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Charcot Marie Tooth Disease ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

scholarly journals A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL

2021 ◽  
Vol 14 ◽  
Author(s):  
Dominik Fröhlich ◽  
Marisa I. Mendes ◽  
Andrew J. Kueh ◽  
Andre Bongers ◽  
Marco J. Herold ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Knockout Mice ◽  
Clinical Picture ◽  
Late Onset ◽  
Adult Life ◽  
Trna Synthetase ◽  
Myelin Proteins ◽  
Motor Deficits ◽  
Postnatal Life

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene DARS1. The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. Dars1 knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing Dars1D367Y point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed Dars1D367Y/D367Y mice with Dars1-null carriers. The resulting Dars1D367Y/− offspring displayed a strong developmental delay compared to control Dars1D367Y/+ littermates, starting during embryogenesis. Only a small fraction of Dars1D367Y/− mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few Dars1D367Y/− mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, Dars1D367Y/− mice remained smaller and lighter than their Dars1D367Y/+ littermates. Despite this early developmental deficit, once they made it through early adolescence Dars1D367Y/− mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in Dars1D367Y/− mice compared to controls. Taken together, Dars1D367Y/− mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in Dars1 knockout mice, and can be leveraged to test potential HBSL therapeutics including DARS1 gene replacement therapy.

scholarly journals Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Amena Smith Fine ◽  
Christina L. Nemeth ◽  
Miriam L. Kaufman ◽  
Ali Fatemi
Keyword(s):  
White Matter ◽  
Developmental Disorders ◽  
Phenotypic Variability ◽  
Disease Onset ◽  
Trna Synthetase ◽  
Compound Heterozygous ◽  
Aminoacyl Trna Synthetase ◽  
Mitochondrial Translation ◽  
White Matter Tracts ◽  
Organ Systems

Abstract Background The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. Body The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. Conclusion The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.

scholarly journals No Enzyme Activity of 25-Hydroxyvitamin D3 1α-Hydroxylase Gene Product in Pseudovitamin D Deficiency Rickets, Including That with Mild Clinical Manifestation

1999 ◽  
Vol 84 (11) ◽  
pp. 4111-4117 ◽  
Author(s):  
Sachiko Kitanaka ◽  
Akiko Murayama ◽  
Toshiyuki Sakaki ◽  
Kuniyo Inouye ◽  
Yoshiki Seino ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Clinical Manifestation ◽  
Phenotypic Variation ◽  
Compound Heterozygous ◽  
Splicing Mutation ◽  
Missense Mutations ◽  
Residual Enzyme Activity ◽  
Mild Phenotype ◽  
Hydroxylase Gene ◽  
Deficiency Rickets

Pseudovitamin D deficiency rickets (PDDR) is an autosomal recessive disorder caused by defect in the activation of vitamin D. We recently isolated 25-hydroxyvitamin D3 1α-hydroxylase gene and identified four homozygous inactivating missense mutations in this gene by analysis of four typical cases of PDDR. This disease shows some phenotypic variation, and it has been suspected that patients with mild phenotypes have mutations that do not totally abolish the enzyme activity. To investigate the molecular defects associated with the phenotypic variation, we analyzed six additional unrelated PDDR patients: one with mild and five with typical clinical manifestation. By sequence analysis, all six patients were proven to have mutations in both alleles. The mutations varied, and we identified four novel missense mutations, a nonsense mutation, and a splicing mutation for the first time. The patient with mild clinical symptoms was compound heterozygous for T321R and a splicing mutation. The splice site mutation caused intron retention. Enzyme activity of the T321R mutant was analyzed by overexpressing the mutant 1α-hydroxylase in Escherichia coli cells to detect the subtle residual enzyme activity. No residual enzyme activity was detected in T321R mutant or in the other mutants. These results indicate that all of the patients, including those of mild phenotype, are caused by 1α-hydroxylase gene mutations that totally abolish the enzyme activity.

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA

2012 ◽  
Vol 441 (3) ◽  
pp. 955-962 ◽  
Author(s):  
Laura van Berge ◽  
Stephanie Dooves ◽  
Carola G.M. van Berkel ◽  
Emiel Polder ◽  
Marjo S. van der Knaap ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Brain Stem ◽  
Cell Lines ◽  
Trna Synthetase ◽  
Neural Cell ◽  
Cell Type ◽  
White Matter Tracts ◽  
Spinal Cord Involvement ◽  
Neural Cell Lines

LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) is an autosomal recessive white matter disorder with slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction. Magnetic resonance imaging shows characteristic abnormalities in the cerebral white matter and specific brain stem and spinal cord tracts. LBSL is caused by mutations in the gene DARS2, which encodes mtAspRS (mitochondrial aspartyl-tRNA synthetase). The selective involvement of specific white matter tracts in LBSL is striking since this protein is ubiquitously expressed. Almost all LBSL patients have one mutation in intron 2 of DARS2, affecting the splicing of the third exon. Using a splicing reporter construct, we find cell-type-specific differences in the sensitivity to these mutations: the mutations have a larger effect on exon 3 exclusion in neural cell lines, especially neuronal cell lines, than in non-neural cell lines. Furthermore, correct inclusion of exon 3 in the normal mtAspRS mRNA occurs less efficiently in neural cells than in other cell types, and this effect is again most pronounced in neuronal cells. The combined result of these two effects may explain the selective vulnerability of specific white matter tracts in LBSL patients.

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