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.
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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
References
Abdel-Salam G, Thoenes M, Afifi HH, Körber F, Swan D, Bolz HJ (2014) The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration. Orphanet J Rare Dis 9(1):12
Akawi NA, Al-Jasmi F, Al-Shamsi AM, Ali BR, Al-Gazali L (2013a) LINS, a modulator of the WNT signaling pathway, is involved in human cognition. Orphanet J Rare Dis 8:87
Akawi N, Ali B, AL Gazali L (2013b) A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2. Birth Defects Res A Clin Mol Teratol 97(7):456–462
Akawi NA, Canpolat FE, White SM, Quilis-Esquerra J, Morales Sanchez M, Gamundi MJ, Mochida GH, Walsh CA, Ali BR, Al-Gazali L (2013c) Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Hum Mutat 34(3):498–505
Al-Gazali L, Ali BR (2010) Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE). Hum Mutat 31(5):505–520
Al-Gazali Lihadh, Hanan H (2014) Consanguinity and Dysmorphology in Arabs. Human Hereditary
Aqeilan RI, Trapasso F, Hussain S, Costinean S, Marshall D, Pekarsky Y, Hagan JP, Zanesi N, Kaou M, Stein GS et al (2007) Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A 104(10):3949–3954
Bednarek AK, Laflin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM (2000) WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res 60(8):2140–2145
Bednarek AK, Keck-Waggoner CL, Daniel RL, Laflin KJ, Bergsagel PL, Kiguchi K, Brenner AJ, Aldaz CM (2001) WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res 61(22):8068–8073
Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V et al (2011) A copy number variation morbidity map of developmental delay. Nat Genet 43(9):838–846
Gribaa M, Salih M, Anheim M, Lagier-Tourenne C, H’mida D, Drouot N, Mohamed A, Elmalik S, Kabiraj M, Al-Rayess M et al (2007) A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23. Brain 130(Pt 7):1921–1928
Iatan I, Choi HY, Ruel I, Reddy MV, Kil H, Lee J, Odeh MA, Salah Z, Abu-Remaileh M, Weissglas-Volkov D et al (2014) The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet 7(4):491–504
Li J, Liu J, Ren Y, Yang J, Liu P (2014) Common chromosomal fragile site gene WWOX in metabolic disorders and tumors. Int J Biol Sci 10(2):142–148
Mallaret M, Synofzik M, Lee J, Sagum CA, Mahajnah M, Sharkia R, Drouot N, Renaud M, Klein FA, Anheim M et al (2014) The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 137(Pt 2):411–419
Reiff RE, Ali BR, Baron B, Yu TW, Ben-Salem S, Coulter ME, Schubert CR, Hill RS, Akawi NA, Al-Younes B et al. (2014) METTL23, a transcriptional partner of GABPA, is essential for human cognition. Hum Mol Genet
Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I et al (2012) Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 91(6):1073–1081
White S, Hewitt J, Turbitt E, van der Zwan Y, Hersmus R, Drop S, Koopman P, Harley V, Cools M, Looijenga L et al (2012) A multi-exon deletion within WWOX is associated with a 46, XY disorder of sex development. Eur J Hum Genet 20(3):348–351
Woods CG, Cox J, Springell K, Hampshire DJ, Mohamed MD, McKibbin M, Stern R, Raymond FL, Sandford R, Malik Sharif S et al (2006) Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet 78(5):889–896
Acknowledgments
We are indebted to the family for their participation in this study. We are grateful to Ms. Saniya Hamad for blood collection. We are thankful to Mayo Clinic that carried out the CMA analysis. We also thank UAEU for their financial support (grant number NP/13/45).
Conflict of Interest
All authors have declared that no competing interests exist.
Author’s Contribution
SBS and BA designed the experimental plan, analyzed the data and wrote the manuscript. SBS performed mutation screening and expression analysis. AJ performed Sanger sequencing. AA helped in the clinical evaluation and blood sample collections. LA identified family and performed the clinical evaluation. All authors read and approved the final manuscript.
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Ben-Salem, S., Al-Shamsi, A.M., John, A. et al. A Novel Whole Exon Deletion in WWOX Gene Causes Early Epilepsy, Intellectual Disability and Optic Atrophy. J Mol Neurosci 56, 17–23 (2015). https://doi.org/10.1007/s12031-014-0463-8
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DOI: https://doi.org/10.1007/s12031-014-0463-8