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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

Variant

Zygosity

Cases/Families

Diagnosis, clinical features

Age of onset

Functional studies

Gain/loss of function

References

p.Asn71Tyr

c.211A > T

HT

1 Taiwanese family

CMT2 a

Slowly progressing sensorimotor LE and UE neuropathy

NCV: intermediateb

11-45y

Not localized in cytoplasm but in organelles, formation of aggregates, growth inhibition, aminoacylation severely defective

 

[37] [23] [19]

p.Lys81Thr

c.242A > C

compound HTc

2 mixed-European descent siblings

Microcephaly, epileptic encephalopathy with persistent myelination defect

Congenital, 3mo

Aminoacylation mildly defective, reduced yeast cell survival

LoF

[31]

p.Gly102Arg

c304G > C

HT

1 North American family

Mild axonal neuropathy with hyperreflexia indicating superimposed myelopathy

NCV: Normal or slight decrease

Third to fifth decade of life

No yeast cell growth

LoF

[24]

p.Arg326Trp

c.976GC > T

HT

1 Dutch family

CMT2N

Severe motor (sensorimotor) LE polyneuropathy with axonal and demyelinating, or pure axonal features

NCV: intermediate or normal

First to third decade of life

No yeast cell growth, toxicity in zebrafish embryos, with aberrant morphology and neurologic phenotype

LoF

[41]

p.Arg329His

c.986G > A

HT

2 French families

CMT2

Sensorimotor LE or LE and UE axonal neuropathy,

NCV: slight to moderate decrease

6-54y

 

LoF

[14]

1 Australian family

CMT2N

Axonal sensorimotor neuropathy and variable sensorineural deafness

NCV: intermediate

Early onset

Aminoacylation severely defective

[23]

5 British families

CMT2

sensorimotor poly- or LE neuropathy

NCV: intermediate

Congenital to 30y

 

[5]

p.Glu337Lys

c.1009G > A

HT

1 family

CMT2

Severe sensorimotor polyneuropathy with axonal and demyelinating features

NCV: moderate decrease

First to third decade of life

Increased yeast growth, increased aminoacylation efficiency, toxicity in zebrafish embryos, with aberrant morphology and neurologic phenotype

GoF

[41]

p.Ser627Leu

c.1880C > T

HT

1 family

CMT2N

Severe axonal sensorimotor LE and UE neuropathy, predominantly distal

NCV: intermediate

Third decade of life

Reduced yeast viability; toxicity in zebrafish embryos, with aberrant morphology and neurologic phenotype

LoF

[41]

p.Glu688Gly

c.2063A > G

HT

1 British family

CMT2 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 HTd

2 mixed-European descent sisters

Progressive microcephaly, MRI shows hypomyelination; epileptic encephalopathy; spastic paraplegia

Congenital

Reduced protein expression, reduced aminoacylation activity, reduced editing activity, accumulation of [3H]Ser-tRNA Ala

LoF

[25]

p.Arg751Gly

c.2251A > G

compound HTc, HM

1 mixed-European descent individual

Microcephaly, epileptic encephalopathy with persistent myelination defect

Congenital, 3mo

Aminoacylation severely defective, normal editing activity, normal yeast survival

LoF

[27]

p.Glu778Ala

c.2333A > C

HT

1 Australian family

Possible 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.Asp893Asn

HT

1 Chinese family

Distal 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 HTd

2 mixed-European descent sisters

Progressive microcephaly, hypomyelination, epileptic encephalopathy, spastic paraplegia

Congenital

Reduced 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]