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Expanding the Clinical Phenotype of IARS2-related Mitochondrial Disease

Case Reports

Expanding the Clinical Phenotype of IARS2-related Mitochondrial Disease

Barbara Vona et al. BMC Med Genet.


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, NM_018060.3) 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.

Keywords: Adrenal insufficiency; CAGSSS; Cataracts; Growth hormone deficiency; IARS2; Sensorineural hearing loss; Sensory neuropathy; Skeletal dysplasia; Type II esophageal achalasia.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Ethics Committees at the University of Würzburg (ID: 46/15) and Mashhad University of Medical Sciences (ID: 213917). Informed written consent from the proband and his parents (Family 1) and the parents and three females (Family 2) was obtained prior to initiating our investigation.

Consent for publication

Written consent for publication of medical data and genetic testing results was obtained from the proband and parents in Family 1, as well as the parents and three females in family 2.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Fig. 1
Fig. 1
Pedigree of patient 1, pure-tone audiograms, radiological examinations, and sequence electropherogram. a The proband’s parents are first-degree cousins. There is no family history of CAGSSS. Genotype results for the c.2725C > T variant are represented under the tested individuals. b Pure-tone audiograms from proband 1 at 16 (red) and 20 (blue) years of age reveal stable, sensorineural hearing loss. Right air conduction (circle), unmasked bone conduction (bracket), and masked bone conduction (<) and left air conduction (x) and unmasked bone conduction (>) are shown from left to right, respectively. c Radiological images depicting epiphyseal dysplasia of the distal radius and fingers with tapering (left) and right hip with shortened femoral neck due to metaphyseal dysplasia (right). d Electropherograms of the homozygous proband (upper panel) and representative heterozygous electrophenogram from a parent (lower panel) showing the nucleotide and amino acid exchange. The variant position is marked with a red arrow
Fig. 2
Fig. 2
Pedigree of patients 2 and 3, radiological examinations, and sequence electropherogram. a The proband’s parents are first-degree cousins. There is no family history of CAGSSS. Genotype results for the c.2282A > G variant are represented under the tested individuals. b Radiological images showing that the first metacarpale bone of the right hand (left) projects short and stunted and the plane x-ray the hyperextension of the metacarpophalangeal and the carpophalangeal joints of the thumb is noticeable. The carpal bones show some mild dysplasia and flattening and tapering of the distal phalanges is visible. Some mild dysplasia of the acetabulum is noticeable (right). On both sides a distinct cross over sign is visible. The femoral heads showing some irregular shape with flattened appearance known as pistol grip deformity. The femoral neck seems shortened in comparison to the opposite side. c Electropherograms of the homozygous proband (upper panel) and representative heterozygous electropherogram (lower panel) showing the nucleotide and amino acid exchange. The variant position is marked with a red arrow
Fig. 3
Fig. 3
IARS2 scheme, sequence alignment and homology model. a Sequence alignment among vertebrates (H. sapiens, NP_060530.3; M. musculus, NM_198653.2; C. anna, XM_008492093.1; G. gallus, NM_001006397.1; C. mydas, XM_007064764.1; X. tropicalis, NM_001127043.1; L. chalumnae, XM_005998405.2; D. rerio, XM_021467083.1) around the sites of the missense mutations discussed in the text (Glu708Lys, His761Arg, Gly874Arg, Pro909Leu, and Pro909Ser). Residues that are invariant in this group of organisms are shown in gray. b Schematic view of IARS2 protein indicating mutations (those reported in this study and the published ones) and colored by phenotype. c Homology model of IARS2. The protein ribbon has the same colors that are shown in the functional regions of the protein in panel B. The residues affected by the missense mutations are highlighted by surfaces with the same color scheme as in panel B. The bound cognate tRNA (tRNAIle) is shown as ribbon and sticks in light orange, and the Ile-AMP analogue as yellow sticks
Fig. 4
Fig. 4
Biochemical and western blot analyses of patient fibroblasts. a Activity of mitochondrial respiratory complexes in control (red) and patient (blue) fibroblast samples. Mean enzyme activities normalised to citrate synthase (CS) of control fibroblasts (n = 8) are set to 100% and error bars represent standard deviation. b Western blots of protein lysate from patient fibroblasts (P) and two age-matched controls (C1 and C2) immunodecorated with antibodies against IARS2, NDUFB8 (CI), UQCRC2 (CIII), COXI (CIV), COXII (CIV) and ATP5A (CV). SDHA and SDHB (CII) were used as loading controls

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