A Multi-exon Deletion Within WWOX is Associated with a 46,XY Disorder of Sex Development

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2011 Nov 11

PMID 22071891

Citations 20

Authors

Stefan White

Jacqueline Hewitt

Erin Turbitt

Yvonne van der Zwan

Remko Hersmus

Stenvert Drop

Peter Koopman

Vincent Harley

Martine Cools

Leendert Looijenga

Andrew Sinclair

Affiliations

Soon will be listed here.

Abstract

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development.

Citing Articles

Whole-genome de novo sequencing reveals genomic variants associated with differences of sex development in SRY negative pigs.

Wu J, Tan S, Feng Z, Zhao H, Yu C, Yang Y Biol Sex Differ. 2024; 15(1):68.

PMID: 39223676 PMC: 11367908. DOI: 10.1186/s13293-024-00644-w.

Testicular differentiation in 46,XX DSD: an overview of genetic causes.

Ferrari M, Silva E, Nishi M, Batista R, Mendonca B, Domenice S Front Endocrinol (Lausanne). 2024; 15():1385901.

PMID: 38721146 PMC: 11076692. DOI: 10.3389/fendo.2024.1385901.

Genetic control of typical and atypical sex development.

Reyes A, Leon N, Frost E, Harley V Nat Rev Urol. 2023; 20(7):434-451.

PMID: 37020056 DOI: 10.1038/s41585-023-00754-x.

WWOX and metabolic regulation in normal and pathological conditions.

Baryla I, Kosla K, Bednarek A J Mol Med (Berl). 2022; 100(12):1691-1702.

PMID: 36271927 PMC: 9691486. DOI: 10.1007/s00109-022-02265-5.

Neurological Disorders Associated with WWOX Germline Mutations-A Comprehensive Overview.

Banne E, Abudiab B, Abu-Swai S, Repudi S, Steinberg D, Shatleh D Cells. 2021; 10(4).

PMID: 33916893 PMC: 8067556. DOI: 10.3390/cells10040824.

References

Hersmus R, Kalfa N, de Leeuw B, Stoop H, Oosterhuis J, de Krijger R . FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). J Pathol. 2008; 215(1):31-8. DOI: 10.1002/path.2335. View

Notini A, Craig J, White S . Copy number variation and mosaicism. Cytogenet Genome Res. 2009; 123(1-4):270-7. DOI: 10.1159/000184717. View

White S, Ohnesorg T, Notini A, Roeszler K, Hewitt J, Daggag H . Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One. 2011; 6(3):e17793. PMC: 3049794. DOI: 10.1371/journal.pone.0017793. View

Aqeilan R, Trapasso F, Hussain S, Costinean S, Marshall D, Pekarsky Y . Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A. 2007; 104(10):3949-54. PMC: 1820689. DOI: 10.1073/pnas.0609783104. View

Cools M, Drop S, Wolffenbuttel K, Oosterhuis J, Looijenga L . Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev. 2006; 27(5):468-84. DOI: 10.1210/er.2006-0005. View

Del Mare S, Salah Z, Aqeilan R . WWOX: its genomics, partners, and functions. J Cell Biochem. 2009; 108(4):737-45. DOI: 10.1002/jcb.22298. View

Cools M, Wolffenbuttel K, Drop S, Oosterhuis J, Looijenga L . Gonadal development and tumor formation at the crossroads of male and female sex determination. Sex Dev. 2011; 5(4):167-80. DOI: 10.1159/000329477. View

Maatouk D, DiNapoli L, Alvers A, Parker K, Taketo M, Capel B . Stabilization of beta-catenin in XY gonads causes male-to-female sex-reversal. Hum Mol Genet. 2008; 17(19):2949-55. PMC: 2536503. DOI: 10.1093/hmg/ddn193. View

Paige A, Taylor K, Taylor C, Hillier S, Farrington S, Scott D . WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci U S A. 2001; 98(20):11417-22. PMC: 58744. DOI: 10.1073/pnas.191175898. View

10.

Aqeilan R, Pekarsky Y, Herrero J, Palamarchuk A, Letofsky J, Druck T . Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci U S A. 2004; 101(13):4401-6. PMC: 384759. DOI: 10.1073/pnas.0400805101. View

11.

Wilhelm D, Palmer S, Koopman P . Sex determination and gonadal development in mammals. Physiol Rev. 2007; 87(1):1-28. DOI: 10.1152/physrev.00009.2006. View

12.

Aqeilan R, Hagan J, de Bruin A, Rawahneh M, Salah Z, Gaudio E . Targeted ablation of the WW domain-containing oxidoreductase tumor suppressor leads to impaired steroidogenesis. Endocrinology. 2008; 150(3):1530-5. PMC: 2654736. DOI: 10.1210/en.2008-1087. View

13.

Stoop H, Honecker F, van de Geijn G, Gillis A, Cools M, de Boer M . Stem cell factor as a novel diagnostic marker for early malignant germ cells. J Pathol. 2008; 216(1):43-54. DOI: 10.1002/path.2378. View

14.

Ludes-Meyers J, Kil H, Nunez M, Conti C, Parker-Thornburg J, Bedford M . WWOX hypomorphic mice display a higher incidence of B-cell lymphomas and develop testicular atrophy. Genes Chromosomes Cancer. 2007; 46(12):1129-36. PMC: 4143238. DOI: 10.1002/gcc.20497. View

15.

Bouteille N, Driouch K, Hage P, Sin S, Formstecher E, Camonis J . Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein. Oncogene. 2009; 28(28):2569-80. DOI: 10.1038/onc.2009.120. View

16.

Sutton E, Hughes J, White S, Sekido R, Tan J, Arboleda V . Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest. 2010; 121(1):328-41. PMC: 3007141. DOI: 10.1172/JCI42580. View

17.

Looijenga L, Stoop H, de Leeuw H, de Gouveia Brazao C, Gillis A, van Roozendaal K . POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003; 63(9):2244-50. View

18.

Nunez M, Ludes-Meyers J, Aldaz C . WWOX protein expression in normal human tissues. J Mol Histol. 2006; 37(3-4):115-25. PMC: 4144810. DOI: 10.1007/s10735-006-9046-5. View

19.

Lee P, Houk C, Ahmed S, Hughes I . Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006; 118(2):e488-500. DOI: 10.1542/peds.2006-0738. View

20.

Bednarek A, Laflin K, Daniel R, Liao Q, Hawkins K, Aldaz C . WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res. 2000; 60(8):2140-5. View