Translation Disorders

1. Translation Disregulation in Neurodegenerative

Disorders
 Prion /Tau-proteins (initiation factor 2p-elF2α)
repression
 FUS(RNA/DNA binding protein) alters translation
 Amylotropic Lateral Sclerosis(Frontotemporal
dementia)
 Diamond-Blackfan ribosomopathy
 Mitochondrial diseases
Integrated Stress Response+Non-Sense Mediated
mRNA Decay Pathway FUS protein
High levels of Regulatory Up-frameshift (UPF-1/3b)
proteins
Role of elF, FUS in NMD pathway
 A resident at Genetics Clinic was trained for Neuro-,
Psychiatric, Mitochondrial diseases. He reported translational
defects leading to post-translational modification diseases.
 Genetic Test Lab: biopsy tests for Ribosomes, Elongation factors,
Karyotyping and Genome Analysis
 Genetic and Neuropsychiatric Counseling
 Rehabilitation and Behavioral therapy

• Q. Describe the translation disregulation

mechanisms.
• Q. Count the Neurodegenerative,
Neuropsychiatric and Mitochondrial diseases.
ALS Disease: Defect in C9ORF72 RNA Translation
 Translational Inherited PS Diseases

• Translation Disorders cause Inherited Protein

Synthesis Defects due to mRNA elF2B mutation
• Wolkott-Rallison infantile-onset diabetes(ERPERK)
• Diamond-Blackfan Anemia(x-linked Dyskeratosis
Congenita)
• Charcot-Marie-Tooth Disease
• Mitochondrial amino-acyl-tRNA synthase, elF 2/3
• Neurodegenerative diseases
• Cancers
• Infectious diseases
• Cardiovascular diseases
 Mitochondrial Translation Defects

• Mitochondrial tRNA mutations, aminoacyl-

tRNA synthase, Ribosomal protein disorders
• Defects in mitochondrial genome encoding 37
genes for respiratory complexes I,III,IV,V
tRNA,rRNA,ribosomal proteins,Translocase
motor defectsMutations in
rRNA,tRNA,ribosomes,amino-acyl synthase
• MELAS due to mito tRNA gene-Leu-1
• MERRF
Gene
Mitochondrial Translation Diseases
Alternative name Clinical phenotype(s)
MTTA mt-tRNA-Ala Myotonic dystrophy-like myopathy; mitochondrial myopathy
MTTC mt-tRNA-Cys MELAS; dystonia
MTTD mt-tRNA-Asp Myopathy
MTTE mt-tRNA-Glu MIDD; transient infantile mitochondrial myopathy
MTTF mt-tRNA-Phe MELAS; MERRF; myopathy; epilepsy; encephalopathy; tubulointerstitial
nephropathy
MTTG mt-tRNA-Gly Hypertrophic cardiomyopathy; exercise intolerance; sudden death
MTTH mt-tRNA-His Cardiomyopathy; RP; MERRF; MELAS; NSHL
MTTI mt-tRNA-lle Cardiomyopathy; familial hypertrophic cardiomyopathy; CPEO
MTTK mt-tRNA-Lys MERRF; cardiomyopathy and deafness; neurogastrointestinal
encephalomyopathy; MIDD; progressive external ophthalmoplegia with
myoclonus
MTTL1 mt-tRNA-Leu (UUR) MELAS; MERRF; cardiomyopathy with or without skeletal myopathy;
encephalopmyopathy; CPEO; Kearns-Sayre syndrome; sudden infant death
syndrome; Leigh syndrome; MIDD; SNHL; FSGS
MTTL2 mt-tRNA-Leu (CUN) Encephalomyopathy; myopathy; cardiomyopathy
MTTM mt-tRNA-Met Myopathy
MTTN mt-tRNA-Asn CPEO; myopathy
MTTP mt-tRNA-Pro Myopathy; MERFF
MTTQ mt-tRNA-Gln Myopathy; sensorineural deafness and migraine; MELAS
MTTR mt-tRNA-Arg Encephalomyopathy
MTTS1 m-tRNA-Ser (UCN) MERRF; MELAS; palmoplantar keratoderma with deafness; NSHL; exercise
intolerance
MTTS2 mt-tRNA-Ser (AGY) Cerebellar ataxia, cataract, and diabetes mellitus; MERRF; MELAS
MTTT mt-tRNA-Thr Fatal infantile myopathy; myopathy
MTTV mt-tRNA-Val Ataxia, progressive seizures, mental deterioration, and hearing loss; Leigh
syndrome; hypertrophic cardiomyopathy; MELAS
MTTW mt-tRNA-Trp Encephalopathy; myopathy; neurogastrointestinal syndrome;
encephalocardiomyopathy; Leigh syndrome
MTTY mt-tRNA-Tyr Exercise intolerance; CPEO with myopathy; FSGS and dilated cardiomyopathy
Clinical phenotypes of Mitochondrial -ARS disorders
Gene Inheritance OMIM Main organ(s) OMIM Phenotype Age at
Mutation phenotype affected onset
AARS2 SNV Recessive 614096 Heart Hypertrophic cardiomyopathy Infancy
AARS2 SNV Recessive 615889 Brain, ovaries Progressive leukoencephalopathy with ovarian Childhood-
failure adulthood
CARS2 SNV Recessive 616672 Brain, muscle Combined oxidative phosphorylation deficiency, 27 Neonatal-
childhood
DARS2 SNV Recessive 611105 Brain Leukoencephalopathy with brainstem and spinal Childhood-
cord involvement and lactate elevation adulthood
EARS2 SNV Recessive 614924 Brain Combined oxidative phosphorylation deficiency, 12 Infancy
FARS2 SNV Recessive 614946 Brain Combined oxidative phosphorylation deficiency, 14 Infancy
FARS2 SNV Recessive 617046 Bran Spastic paraplegia 77, autosomal recessive Infancy-
childhood
HARS2 SNV Recessive 614926 Cochlea, ovaries Perrault syndrome, 2 Childhood-
adulthood
IARS2 SNV Recessive 616007 Brain, bone, Cataracts, growth hormone deficiency, sensory Infancy
eyes neuropathy, sensiorineural hearing loss, and skeletal
dysplasia
LARS2 SNV Recessive 615300 Cochlea, ovaries Perrault syndrome, 4 Childhood-
adulthood
LARS2 SNV Recessive 617021 Brain, blood Hydrops, lactic acidosis, and sideroblastic anemia Neonatal
MARS2 CNV Recessive 611390 Brain Spastic ataxia 3, autosomal recessive Childhood-
adulthood
MARS2 SNV Recessive 616430 Brain, muscle Combined oxidative phosphorylation deficiency, 25 Infancy
NARS2 SNV Recessive 616239 Brain, muscle, Combined oxidative phosphorylation deficiency, 24 Infancy
cochlea
NARS2 SNV Recessive 618434 Cochlea Deafness, autosomal recessive 94 Infancy
PARS2 SNV Recessive 618437 Brain Epilepetic encephalopathy, early infantile, 75 Neonatal-
infancy
RARS2 SNV Recessive 611523 Brain Pontocerebellar hypoplasia, type 6 Infancy-
childhood
SARS2 SNV Recessive 613845 Kidney Tubulopathy (hyperuricemia, metabolic alkalosis), Infancy
pulmonary hypertension, and progressive renal
failure (HUPRA syndrome)
TARS2 SNV Recessive 615918 Brain, muscle Combined oxidative phosphorylation deficiency, 21 Neonatal
VARS2 SNV Recessive 615917 Brain, muscle Combined oxidative phosphorylation deficiency, 20 Infancy
WARS2 SNV Recessive 617710 Brain, muscle Neurodevelopmental disorder, mitochondria, with Infancy
abnormal movements and lactic acidosis, with or
without seizures
YARS2 SNV Recessive 613561 Muscle, blood MLASA Infancy-
* childhood
GARS* SNV Dominant 601472 Nerves Charcot Marie Tooth disease, type 2D Adulthood
GARS* SNV Dominant 600794 Nerves Neuronopathy, distal hereditary motor, type VA Adulthood
GARS SNV Recessive N/A Brain, heart Cardiomyopathy or growth retardation and complex Neonatal-
* neurological presentation childhood
KARS SNV Recessive 613641 Nerves Charcot Marie Tooth disease, recessive Childhood
20920668

*
intermediate, B
 Translation Psychiatric Disorders

• CNS dendritic protein translation regulate mRNA

localization, initiation, termination for synaptic
plasticityelF2α/1A-GTP controlcognitive,
learning,memory functions,Schzophrenia,
Depression, Bipolar disorders, Addiction
Biochemical basis of Freidreich Ataxia
arkinson Disease: α-Synuclein in Astrocyte