Journal of Molecular Neuroscience

, Volume 56, Issue 1, pp 17–23 | Cite as

A Novel Whole Exon Deletion in WWOX Gene Causes Early Epilepsy, Intellectual Disability and Optic Atrophy

  • Salma Ben-Salem
  • Aisha M. Al-Shamsi
  • Anne John
  • Bassam R. Ali
  • Lihadh Al-Gazali
Article

Abstract

Recent studies have implicated the WW domain-containing oxidoreductase encoding gene (WWOX) in a severe form of autosomal recessive neurological disorder. This condition showed an overlapping spectrum of clinical features including spinocerebellar ataxia associated with generalized seizures and delayed psychomotor development to growth retardation, spasticity, and microcephaly. We evaluated a child from a consanguineous Emirati family that presented at birth with growth retardation, microcephaly, epileptic seizures, and later developed spasticity and delayed psychomotor development. Screening for deletions and duplications using whole-chromosomal microarray analysis identified a novel homozygous microdeletion encompassing exon 5 of the WWOX gene. Analysis of parental DNA indicated that this deletion was inherited from both parents and lies within a large region of homozygosity. Sanger sequencing of the cDNA showed that the deletion resulted in exon 5 skipping leading to a frame-shift and creating a premature stop codon at amino acid position 212. Quantification of mRNA revealed striking low level of WWOX expression in the child and moderate level of expression in the mother compared to a healthy control. To the best of our knowledge, this is the first homozygous germline structural variation in WWOX gene resulting in truncated transcripts that were presumably subject to NMD pathway. Our findings extend the clinical and genetic spectrum of WWOX mutations and support a crucial role of this gene in neurological development.

Keywords

Whole-chromosomal microarray WWOX Microdeletion Microcephaly ID 

Abbreviations

bp

Base pair

cDNA

Complementary deoxyribonucleic acid

CSF

Cerebrospinal fluid

CT

Cycle threshold

CMA

Chromosomal micro-array

CNV

Copy number variation

DNA

Deoxyribonucleic acid

dNTPs

Deoxyribonucleotide triphosphates

Dvl2

Dishevelled segment polarity protein 2

EDTA

Ethylenediaminetetraacetic acid

EEG

Electroencephalography

ERBB4

Erythroblastic leukemia viral oncogene homolog 4

HD

High definition

HPRT

Hypoxanthine phosphoribosyltransferase 1

Kb

Kilobase

mRNA

messenger ribonucleic acid

NMD

Non-sense mediated decay

PCR

Polymerase chain reaction

p73

Tumor suppressor p73

RQ

Relative quantification

RNA

Ribonucleic acid

RT

Reverse transcriptase

RUNX2

Runt-related transcription factor 2

SD

Standard deviation

SIMPLE/LITAF

Lipopolysaccharide-induced tumor necrosis factor-alpha factor

UAE

United Arab Emirates

USA

United States of America

WT

Wild Type

WW

The rsp5-domain or WWP repeating motif

WWOX

WW domain-containing oxidoreductase

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Salma Ben-Salem
    • 1
  • Aisha M. Al-Shamsi
    • 2
  • Anne John
    • 1
  • Bassam R. Ali
    • 1
  • Lihadh Al-Gazali
    • 3
  1. 1.Department of Pathology, College of Medicine and Heath SciencesUnited Arab Emirates UniversityAl-AinUnited Arab Emirates
  2. 2.Department of PaediatricsTawam HospitalAl-AinUnited Arab Emirates
  3. 3.Department of Paediatrics, College of Medicine and Heath SciencesUnited Arab Emirates UniversityAl-AinUnited Arab Emirates

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