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

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.

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

“…Few genes are known to underlie recessive forms of IEE. WWOX has been pointed as one of them in one family study to date 20. We provide data substantially confirming this finding in five patients from four families.…”

“…The phenotype in the second family ‘closely resembled the index family’,14 which allowed validating WWOX mutations in SCAR12. In contrast, the developmental phenotype of affected individuals in the third consanguineous family was much more severe 20. Indeed, the two affected siblings never acquired any developmental milestone and died before 2 years.…”

“…Prior to this study, biallelic germline anomalies of WWOX were found in seven children (and suspected in one sibling) from three families 14 20. All patients had developmental retardation or intellectual deficiency and neurological manifestations, albeit with different degrees of severity.…”

HACE1deficiency causes an autosomal recessive neurodevelopmental syndrome

“…Another putative tumour suppressor gene recently shown to be mutated in a neurodevelopmental syndrome is WWOX. 15 16 Again, in these studies patients homozygous for loss-of-function mutations, as well as carriers, showed no cancer predisposition.…”

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

“…The WWOX-associated phenotype displays a wide range of phenotypic abnormalities which might be related to the nature of mutations; point mutations (such as p.P47T, p.P47R, p.G372R) are usually associated with milder phenotypes than those associated with nonsense mutations (such as p.R54*, p.K297*, p.W335*) or partial/complete deletions (Abu-Remaileh et al 2015). Nonsense or null mutations exhibited severe phenotype including progressive microcephaly, severe early onset spasticity, infantile epileptic encephalopathy, optic atrophy, failure to thrive, and premature death or abortion (Abdel-Salam et al 2014, Ben-Salem et al 2015, Tabarki et al 2015, while missense mutations in our patients and others cause a milder phenotype with no progressive microcephaly, no spasticity or spasticity with exaggerated reflexes (Mallaret et al 2014). Interestingly, neither our patients nor others had developed tumors, however, this does not negate a cumulative lifespan risk to develop cancer.…”