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A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay

Published on Aug 1, 2018in Neurogenetics3.017
· DOI :10.1007/s10048-018-0549-5
Jessika Johannsen6
Estimated H-index: 6
(UHH: University of Hamburg),
Fanny Kortüm10
Estimated H-index: 10
(UHH: University of Hamburg)
+ 4 AuthorsRené Santer26
Estimated H-index: 26
(UHH: University of Hamburg)
Abstract
The human WWOX (WW domain-containing oxidoreductase) gene, originally known as a tumor suppressor gene, has been shown to be important for brain function and development. In recent years, mutations in WWOX have been associated with a wide phenotypic spectrum of autosomal recessively inherited neurodevelopmental disorders. Whole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. Functional WWOX analysis was performed in fibroblasts of one patient. Transcription and translation were assessed by quantitative real-time PCR and Western blotting. We report two related patients who presented with early epilepsy refractory to treatment, progressive microcephaly, profound developmental delay, and brain MRI abnormalities. Additionally, one of the patients showed bilateral optic atrophy. Whole exome sequencing revealed homozygosity for a novel missense variant affecting the evolutionary conserved amino acid Gln230 in the catalytic short-chain dehydrogenase/reductase (SDR) domain of WWOX in both girls. Functional studies showed normal levels of WWOX transcripts but absence of WWOX protein. To our knowledge, our patients are the first individuals presenting the more severe end of the phenotypic spectrum of WWOX deficiency, although they were only affected by a single missense variant of WWOX. This could be explained by the functional data indicating an impaired translation or premature degradation of the WWOX protein.
  • References (21)
  • Citations (4)
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References21
Newest
#2Aaron M. WengerH-Index: 14
Last. Gill BejeranoH-Index: 35
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Gill Bejerano and colleagues present M-CAP, a classifier that estimates variant pathogenicity in clinical exome data sets. They show that M-CAP outperforms other existing methods at all thresholds and correctly dismisses 60% of rare missense variants of uncertain significance at 95% sensitivity.
205 CitationsSource
#1Nilah M. Ioannidis (Stanford University)H-Index: 4
#2Joseph H. Rothstein (Stanford University)H-Index: 18
Last. Weiva Sieh (Stanford University)H-Index: 26
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The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of indivi...
229 CitationsSource
#1Markus A. Schirmer (GAU: University of Göttingen)H-Index: 5
#2Claudia M. Lüske (GAU: University of Göttingen)H-Index: 1
Last. B. Michael Ghadimi (GAU: University of Göttingen)H-Index: 28
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Background: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects.
9 CitationsSource
#1Brahim TabarkiH-Index: 17
#2Amal AlhashemH-Index: 15
Last. Giulio Zuccoli (University of Pittsburgh)H-Index: 19
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Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A) of WWOX in all ...
15 CitationsSource
#1Chun-I SzeH-Index: 21
#2Yu-Min KuoH-Index: 46
Last. Nan-Shan ChangH-Index: 26
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A cascade of protein aggregation bombards mitochondria for neurodegeneration and apoptosis under WWOX deficiency
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#1Fanny Kortüm (UHH: University of Hamburg)H-Index: 10
#2Viviana CaputoH-Index: 19
Last. Kerstin Kutsche (UHH: University of Hamburg)H-Index: 32
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Kerstin Kutsche, Marco Tartaglia and colleagues show that missense mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome, a disorder characterized by facial dysmorphism, intellectual disability, digit anomalies and hypertrichosis. Functional studies indicate that the KCNH1 mutations lead to altered channel activity.
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#1Salma Ben-Salem (United Arab Emirates University)H-Index: 8
#2Aisha M. Al-ShamsiH-Index: 8
Last. Lihadh Al-Gazali (United Arab Emirates University)H-Index: 49
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24 CitationsSource
#1Brahim TabarkiH-Index: 17
#2Fuad Al MutairiH-Index: 8
Last. Amal Al HashemH-Index: 11
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WWOX was cloned as a tumor suppressor gene mapping to chromosomal fragile site FRA16D. Loss of WWOX is closely related to tumorigenesis, cancer progression, and therapy resistance. Recent studies demonstrate the growing role of WWOX gene in other human pathologies such as metabolic and nervous system-related conditions. The neurologic phenotype of WWOX mutation includes seizures, ataxia, developmental delay, and spasticity of variable severity. WWOX is a ubiquitous protein with high expression i...
12 CitationsSource
#1Cyril MignotH-Index: 24
#2Laetitia LambertH-Index: 11
Last. Christophe Philippe (University of Lorraine)H-Index: 31
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Background Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling. Methods By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX . Results We i...
30 CitationsSource
#1Hsin Tzu Chang (NCKU: National Cheng Kung University)H-Index: 1
#2Chan Chuan Liu (NCKU: National Cheng Kung University)H-Index: 2
Last. Chun-I SzeH-Index: 21
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// Hsin-Tzu Chang 1 , Chan-Chuan Liu 1 , Shur-Tzu Chen 1 , Ye Vone Yap 2 , Nan-Shang Chang 2,3 and Chun-I Sze 1 1 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3 Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan Correspondence: Nan-Shan Chang, email: // Chun-I Sze, email: // Keywords : WWOX, WO...
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Cited By4
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#1Tangfeng Su (HUST: Huazhong University of Science and Technology)
Last. Sanqing Xu (HUST: Huazhong University of Science and Technology)
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Source
#1Chengqing Yang (Qingdao University)H-Index: 1
#1Chengqing YangH-Index: 1
Last. Fei LiH-Index: 1
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Abstract Defects of WW domain-containing oxidoreductase (WWOX) has been associated with autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. The mutations in this gene can lead to global developmental delay, acquired microcephaly, and epilepsy. We report an infant with an autosomal recessive severe early-onset epileptic encephalopathy. Whole exome sequencing analysis was applied to the patient. Novel compound heterozygous mutations in the W...
2 CitationsSource
The brain is the most functionally organized structure of all organs. It manages behavior, perception and higher cognitive functions. The WWOX gene is non classical tumor suppressor gene, which has been shown to have an impact on proliferation, apoptosis and migration processes. Moreover, genetic aberrations in WWOX induce severe neuropathological phenotypes in humans and rodents. The aim of the present study was to investigate in detail the impact of WWOX on human neural stem cell maintenance a...
Source
WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the ef...
Source
#1Hepsen Mine Serin (Ege University)
#2Erdem Simsek (Ege University)
Last. Sarenur Gokben (Ege University)H-Index: 15
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Epileptic encephalopathies are a group of disorders in which epileptiform abnormalities cause progressive deterioration in cerebral function. Genetic causes have been described in several of the epileptic encephalopathies, and many previously unknown genes have been identified. WW domain-containing oxidoreductase (WWOX) has recently been implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. With whole-exome sequencing, we ident...
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