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Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

Bansagi B, Antoniadi T, Burton-Jones S, Murphy SM, McHugh J, Alexander M, Wells R, Davies J, Hilton-Jones D, Lochmüller H, Chinnery P, Horvath R - J. Neurol. (2015)

Bottom Line: The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated.The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly).We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

View Article: PubMed Central - PubMed

Affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

ABSTRACT
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

No MeSH data available.


Related in: MedlinePlus

Sequenced c.986G>A missense mutation in AARS in affected UK and Irish index patients. Illustrated positions of AARS mutations and conservation of affected residues across species
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Fig2: Sequenced c.986G>A missense mutation in AARS in affected UK and Irish index patients. Illustrated positions of AARS mutations and conservation of affected residues across species

Mentions: With the use of IPN 56 gene panel assay we identified the previously described pathogenic variant in exon 8 of the AARS gene (c.986G>A, p.Arg329His) in all 4 UK and in Irish family 1. We identified another AARS variant (c.2063A>G, p.Glu688Gly) which to date has not been reported in the literature, as the cause of the dominant sensorimotor neuropathy manifesting in the second family originated from Ireland. This variant is not recorded in dbSNP, 1000 genomes, Exome Variant Server or Exome Aggregation Consortium. Alignment of protein sequences from multiple species supported that glutamic acid 688 is highly conserved among all species from E.coli to H.sapiens. In silico prediction tools indicate this missense change as likely deleterious (SIFT: deleterious; Polyphen2: probably pathogenic; Mutation Taster disease causing). The variant segregated with disease in this family supporting pathogenicity (Fig. 2).Fig. 2


Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

Bansagi B, Antoniadi T, Burton-Jones S, Murphy SM, McHugh J, Alexander M, Wells R, Davies J, Hilton-Jones D, Lochmüller H, Chinnery P, Horvath R - J. Neurol. (2015)

Sequenced c.986G>A missense mutation in AARS in affected UK and Irish index patients. Illustrated positions of AARS mutations and conservation of affected residues across species
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4539360&req=5

Fig2: Sequenced c.986G>A missense mutation in AARS in affected UK and Irish index patients. Illustrated positions of AARS mutations and conservation of affected residues across species
Mentions: With the use of IPN 56 gene panel assay we identified the previously described pathogenic variant in exon 8 of the AARS gene (c.986G>A, p.Arg329His) in all 4 UK and in Irish family 1. We identified another AARS variant (c.2063A>G, p.Glu688Gly) which to date has not been reported in the literature, as the cause of the dominant sensorimotor neuropathy manifesting in the second family originated from Ireland. This variant is not recorded in dbSNP, 1000 genomes, Exome Variant Server or Exome Aggregation Consortium. Alignment of protein sequences from multiple species supported that glutamic acid 688 is highly conserved among all species from E.coli to H.sapiens. In silico prediction tools indicate this missense change as likely deleterious (SIFT: deleterious; Polyphen2: probably pathogenic; Mutation Taster disease causing). The variant segregated with disease in this family supporting pathogenicity (Fig. 2).Fig. 2

Bottom Line: The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated.The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly).We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

View Article: PubMed Central - PubMed

Affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

ABSTRACT
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

No MeSH data available.


Related in: MedlinePlus