The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration

Ghada Abdel-Salam,Michaela Thoenes,Friederike Körber,Daniel Swan,Hanno Jörn Bolz,Hanan H Afifi

doi:10.1186/1750-1172-9-12

Abstract

BackgroundWWOX, encoding WW domain-containing oxidoreductase, spans FRA16D, the second most common chromosomal fragile site frequently altered in cancers. It is therefore considered a tumor suppressor gene, but its direct implication in cancerogenesis remains controversial.Methods and resultsBy whole-exome sequencing, we identified a homozygous WWOX nonsense mutation, p.Arg54*, in a girl from a consanguineous family with a severe syndrome of growth retardation, microcephaly, epileptic seizures, retinopathy and early death, a phenotype highly similar to the abormalities reported in lde/lde rats with a spontaneous functional null mutation of Wwox. As in rats, no tumors were observed in the patient or heterozygous mutation carriers.ConclusionsOur finding, a homozygous loss-of-function germline mutation in WWOX in a patient with a lethal autosomal recessive syndrome, supports an alternative role of WWOX and indicates its importance for human viability.

Highlights

WWOX, encoding WW domain-containing oxidoreductase, spans FRA16D, the second most common chromosomal fragile site frequently altered in cancers
WWOX has been extensively studied for its role in cancer because it localizes to a common fragile site, FRA16D, a genomic region susceptible to chromosomal rearrangements [1]
Lethality in mice with targeted Wwox ablation has largely prevented studies on tumor susceptibility, focal bone lesions were interpreted as early osteosarcomas

Summary

Introduction

WWOX, encoding WW domain-containing oxidoreductase, spans FRA16D, the second most common chromosomal fragile site frequently altered in cancers. It is considered a tumor suppressor gene, but its direct implication in cancerogenesis remains controversial. WWOX has been extensively studied for its role in cancer because it localizes to a common fragile site, FRA16D, a genomic region susceptible to chromosomal rearrangements [1]. Somatic homozygous WWOX deletions are common in various malignancies. Lethality in mice with targeted Wwox ablation has largely prevented studies on tumor susceptibility, focal bone lesions were interpreted as early osteosarcomas. Some studies in mice with conditional Wwox deletion, did not support the categorization of WWOX as a primary tumor suppressor

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