A novel AARS mutation in a family with dominant myeloneuropathy

Abstract

Objective: To determine the genetic cause of neurodegeneration in a family with myeloneuropathy. Methods:We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.Results: All affected family members had a mild axonal neuropathy, and 3 of 4 had lower extremity hyperreflexia, evidence of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation c.304G.C (p.Gly102Arg) in the alanyl-tRNA synthetase (AARS) gene; this allele was not identified in unaffected individuals or control samples. The equivalent change in the yeast ortholog failed to complement a strain of yeast lacking AARS function, suggesting that the mutation is damaging.Conclusion: A novel mutation in AARS causes a mild myeloneuropathy, a novel phenotype for patients with mutations in one of the tRNA synthetase genes. Charcot-Marie-Tooth disease (CMT) and hereditary motor and sensory neuropathy (HMSN) are alternative names for inherited neuropathies that are not part of more complex syndromes. With an estimated prevalence of 1 in 2,500 persons, CMT/HMSN is one of the commonest neurogenetic diseases and is subdivided according to clinical, electrophysiologic, histologic, and genetic features.1 CMT2/HMSN-II is a dominantly inherited axonal neuropathy, with nerve conduction velocities greater than 38 m/s. Mutations in more than 20 different genes cause autosomal dominant CMT2. With the exception of some MPZ mutations, these mutations are thought to produce a neuropathy through their direct effects in neurons. Mutations in genes that encode aminoacyl-tRNA synthetases (ARS) cause some forms of CMT2. These enzymes charge tRNAs with their cognate amino acids, establishing the genetic code. Mutations in the glycyl-tRNA synthetase (GARS) gene were the first to be described, found in patients with dominant purely motor (hereditary motor neuropathy 5A) or dominant motor predominant (CMT2D) neuropathy. ; and methionyl-tRNA synthetase (MARS) in late-onset, dominant

Human aminoacyl-tRNA synthetases in diseases of the nervous system

“…35 A heterozygous missense mutation G102R in AARS causes only mild axonal neuropathy and lower extremity hyperflexia in 5 siblings. 36 This variant could not complement the ala1 knockout mutant yeast strain, suggesting that Gly102 is important for function and/or structure of AlaRS. Furthermore, heterozygous mutations T132I, P134H, D175E, and D364Y in human HARS cause axonal and demyelinating motor and sensory neuropathies ranging from adult-onset CMT2, CMT1, and typical CMT to HMN.…”

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

“…Indeed, one mutation with strong genetic evidence that has yet to show reduced function in enzyme kinetic or yeast complementation assays (E71G GARS ) [34,65] shows a loss-of-function effect in a fly model (see below) [66], warranting a more detailed characterization of the enzyme activity of the mutant protein. In summary, while caution is required when interpreting the data, yeast complementation assays are currently the most effective and efficient in vivo test for predicting the pathogenicity of ARS mutations [67]. …”

Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy

“…Alanyl‐tRNA synthetase (AARS) is an ARS that was initially implicated in autosomal dominant Charcot‐Marie‐Tooth (CMT) disease (Bansagi et al., ; Latour et al., ; McLaughlin et al., ; Motley et al., ). Recently, biallelic mutations in AARS were identified in three individuals from two families, who presented with early‐onset epileptic encephalopathy (Simons et al., ).…”

“…B). Individuals with CMT2N typically demonstrate distal lower limb‐predominant sensorimotor neuropathy with decreased action potentials indicating primary axonal damage (England et al., ), though several cases with mild associated myelopathy have been reported (Motley et al., ). Recently, biallelic mutations in AARS were reported in three individuals with severe epileptic encephalopathy (Simons et al., ).…”