Expanding the clinical phenotype of IARS2-related mitochondrial disease

Vona, B. and Maroofian, R. and Bellacchio, E. and Najafi, M. and Thompson, K. and Alahmad, A. and He, L. and Ahangari, N. and Rad, A. and Shahrokhzadeh, S. and Bahena, P. and Mittag, F. and Traub, F. and Movaffagh, J. and Amiri, N. and Doosti, M. and Boostani, R. and Shirzadeh, E. and Haaf, T. and Diodato, D. and Schmidts, M. and Taylor, R. W. and Karimiani, E. G. (2018) Expanding the clinical phenotype of IARS2-related mitochondrial disease. BMC medical genetics, 19 (1). p. 196.

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BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.

Item Type: Article
Additional Information: Cited By :1 Export Date: 16 February 2020
Uncontrolled Keywords: Adrenal insufficiency CAGSSS Cataracts Growth hormone deficiency IARS2 Sensorineural hearing loss Sensory neuropathy Skeletal dysplasia Type II esophageal achalasia isoleucine transfer RNA ligase adult amino acid sequence bone dysplasia case report cataract consanguinity disorders of mitochondrial functions female gene expression genetics homozygote human Leigh disease male missense mutation molecular model neuropathy pathology pedigree perception deafness protein conformation protein subunit syndrome whole exome sequencing Bone Diseases, Developmental Hearing Loss, Sensorineural Hereditary Sensory and Autonomic Neuropathies Humans Isoleucine-tRNA Ligase Mitochondrial Diseases Models, Molecular Mutation, Missense Protein Subunits
Subjects: QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 27 Apr 2020 06:54
Last Modified: 27 Apr 2020 06:54
URI: http://eprints.mums.ac.ir/id/eprint/17573

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