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Table 1 Summary of the most informative reports describing mutations in AARS

From: An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids

VariantZygosityCases/FamiliesDiagnosis, clinical featuresAge of onsetFunctional studiesGain/loss of functionReferences
p.Asn71Tyr
c.211A > T
HT1 Taiwanese familyCMT2 a
Slowly progressing sensorimotor LE and UE neuropathy
NCV: intermediateb
11-45yNot localized in cytoplasm but in organelles, formation of aggregates, growth inhibition, aminoacylation severely defective [37] [23] [19]
p.Lys81Thr
c.242A > C
compound HTc2 mixed-European descent siblingsMicrocephaly, epileptic encephalopathy with persistent myelination defectCongenital, 3moAminoacylation mildly defective, reduced yeast cell survivalLoF[31]
p.Gly102Arg
c304G > C
HT1 North American familyMild axonal neuropathy with hyperreflexia indicating superimposed myelopathy
NCV: Normal or slight decrease
Third to fifth decade of lifeNo yeast cell growthLoF[24]
p.Arg326Trp
c.976GC > T
HT1 Dutch familyCMT2N
Severe motor (sensorimotor) LE polyneuropathy with axonal and demyelinating, or pure axonal features
NCV: intermediate or normal
First to third decade of lifeNo yeast cell growth, toxicity in zebrafish embryos, with aberrant morphology and neurologic phenotypeLoF[41]
p.Arg329His
c.986G > A
HT2 French familiesCMT2
Sensorimotor LE or LE and UE axonal neuropathy,
NCV: slight to moderate decrease
6-54y LoF[14]
1 Australian familyCMT2N
Axonal sensorimotor neuropathy and variable sensorineural deafness
NCV: intermediate
Early onsetAminoacylation severely defective[23]
5 British familiesCMT2
sensorimotor poly- or LE neuropathy
NCV: intermediate
Congenital to 30y [5]
p.Glu337Lys
c.1009G > A
HT1 familyCMT2
Severe sensorimotor polyneuropathy with axonal and demyelinating features
NCV: moderate decrease
First to third decade of lifeIncreased yeast growth, increased aminoacylation efficiency, toxicity in zebrafish embryos, with aberrant morphology and neurologic phenotypeGoF[41]
p.Ser627Leu
c.1880C > T
HT1 familyCMT2N
Severe axonal sensorimotor LE and UE neuropathy, predominantly distal
NCV: intermediate
Third decade of lifeReduced yeast viability; toxicity in zebrafish embryos, with aberrant morphology and neurologic phenotypeLoF[41]
p.Glu688Gly
c.2063A > G
HT1 British familyCMT2 pedigree with transitional forms to CMT1
sensorimotor poly- or LE neuropathy; split hand deformity
NCV: intermediate
Congenital to first decade of life  [5]
p.Tyr690Leufs*3
c.2067dupC
compound HTd2 mixed-European descent sistersProgressive microcephaly, MRI shows hypomyelination; epileptic encephalopathy; spastic paraplegiaCongenitalReduced protein expression, reduced aminoacylation activity, reduced editing activity, accumulation of [3H]Ser-tRNA AlaLoF[25]
p.Arg751Gly
c.2251A > G
compound HTc, HM1 mixed-European descent individualMicrocephaly, epileptic encephalopathy with persistent myelination defectCongenital, 3moAminoacylation severely defective, normal editing activity, normal yeast survivalLoF[27]
p.Glu778Ala
c.2333A > C
HT1 Australian familyPossible CMT2N
Rippling muscles, cramps, and polyneuropathy; or only rippling muscles and cramps
NCV: severe axonal lesions
N.A.Normal yeast growth, normal localization, normal aminoacylation, normal editing activity. [23]
p.Asp893AsnHT1 Chinese familyDistal hereditary motor neuropathy (dHMN)
Mild UE weakness, slow progression, no sensibility disturbance. Normal NCV, but EMG with neurogenic lesion
First to sixth decade of life  [42]
p.Gly913Asp
c.2738G > A
compound HTd2 mixed-European descent sistersProgressive microcephaly, hypomyelination, epileptic encephalopathy, spastic paraplegiaCongenitalReduced protein expression, reduced aminoacylation activity, normal editing activity [25]
  1. Other variants identified in the gene but associated with less clinical information or without a confirmed association with disease are presented in Additional file 1. Many CMT2 reports include statements that genes most frequently implicated in CMT were excluded. CMT Charcot-Marie-Tooth disease, CMT2N Charcot-Marie-Tooth disease type 2 N, HT heterozygous mutation, HM homozygous mutation, LoF loss-of-function mutation, GoF gain-of-function mutation, NCV nerve conduction velocity, UE upper extremity, LE lower extremity, EMG electromyography. aAccording to the European CMT consortium diagnostic guidelines bIntermediate NCV defined to be 25–45 m/sec. c Compound heterozygous sample NP_001596:p.[Lys81Thr];[p.Arg751Gly] d Compound heterozygous sample NP_001596:p.[Tyr690Leufs*3];p.[Gly913Asp]