TY  - JOUR
A1  - Doll, Julia
A1  - Kolb, Susanne
A1  - Schnapp, Linda
A1  - Rad, Aboulfazl
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Adli, Abolfazl
A1  - Hasanzadeh, Atefeh
A1  - Liedtke, Daniel
A1  - Knaup, Sabine
A1  - Hofrichter, Michaela AH
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Kong, Il-Keun
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - Novel loss-of-function variants in CDC14A are associated with recessive sensorineural hearing loss in Iranian and Pakistani patients
JF  - International Journal of Molecular Sciences
N2  - CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.
KW  - CDC14A
KW  - DFNB32
KW  - autosomal recessive hearing loss
KW  - exome sequencing
KW  - splicing
KW  - frameshift
KW  - non-sense mediated mRNA decay
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285142
SN  - 1422-0067
VL  - 21
IS  - 1
ER  - 
TY  - JOUR
A1  - Vona, Barbara
A1  - Maroofian, Reza
A1  - Bellacchio, Emanuele
A1  - Najafi, Maryam
A1  - Thompson, Kyle
A1  - Alahmad, Ahmad
A1  - He, Langping
A1  - Ahangari, Najmeh
A1  - Rad, Abolfazl
A1  - Shahrokhzadeh, Sima
A1  - Bahena, Paulina
A1  - Mittag, Falk
A1  - Traub, Frank
A1  - Movaffagh, Jebrail
A1  - Amiri, Nafise
A1  - Doosti, Mohammad
A1  - Boostani, Reza
A1  - Shirzadeh, Ebrahim
A1  - Haaf, Thomas
A1  - Diodato, Daria
A1  - Schmidts, Miriam
A1  - Taylor, Robert W.
A1  - Karimiani, Ehsan Ghayoor
T1  - Expanding the clinical phenotype of IARS2-related mitochondrial disease
JF  - BMC Medical Genetics
N2  - 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.
KW  - adrenal insufficiency
KW  - CAGSSS
KW  - cataracts
KW  - growth hormone deficiency
KW  - IARS2
KW  - sensory neuropathy
KW  - sensorineural hearing loss
KW  - type II esophageal achalasia
KW  - skeletal dysplasia
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176620
VL  - 19
IS  - 196
ER  -