Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity

Abstract

Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

“…Gabor Geza Kovacs, Institute of Neurology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria, e-mail: gabor.kovacs@meduniwien.ac.at encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibres), LHON (Leber's hereditary optic neuropathy), MNGIE (mitochondrial neurogastrointestinal encephalopathy), NARP (neuropathy, ataxia, retini tis pigmentosa), Leigh's syndrome and Kearns-Sayre syndrome (KSS) [4,6,9,47], as well as the more recently characterized LBSL (leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation) [39,48] and HBSL (hypomyelination with brainstem and spinal cord involvement and leg spasticity) [44]. The leading symptoms develop due to the progressive pathology in organs with high energy demand, resulting usually in early death.…”

DARS -associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder

“…1 HBSL was first described in 10 patients, all of whom had a severe presentation with infantile onset and extensive MRI signal abnormalities of the supratentorial white matter suggesting hypomyelination, as well as signal changes in the spinal cord. HBSL affects the same tracts as leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL), 1 a disease caused by mutations in DARS2, encoding the mitochondrial counterpart of AspRS.…”

tRN-A-RS Acts As Biomarker for Cancer and Other Diseases

“…Interestingly, cell proliferation mitogenic signal dissociates MARS from multi-ARS complex and translocates it to nucleoli enhancing rRNA synthetase. Thus, MARS switches its role, synchronizing rRNA synthesis in the nucleolus in proliferative condition and protein synthesis in cytoplasm in normal condition [85]. It is interesting to note that only three ARS2 are linked to cancer.…”

“…Fas ligation dissociates the interaction of QARS and ASK1, thus mediating apoptosis [116]. YARS and RARS secreted from apoptotic tumor cells arrest translation and mediate the production of required cytokines inducing apoptosis [85]. Interestingly, cell proliferation mitogenic signal dissociates MARS from multi-ARS complex and translocates it to nucleoli enhancing rRNA synthetase.…”

“…Glycyl tRNA synthetase, GARS, is mutated in CMT type 2D, CMT2D. GARS was the first synthetase gene discovered to be mutated in human disease [85,86]. p.R329H variant of alanyl tRNA synthetase, AARS, has reduced enzymatic activity and is found to segregate from patient suffering from CMT type 2N, CMT2N [87,88].…”