Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: WWOX
SNOMEDCT: 770898002;
Cytogenetic location: 16q23.1-q23.2 Genomic coordinates (GRCh38): 16:78,099,654-79,212,667 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.1-q23.2 | Developmental and epileptic encephalopathy 28 | 616211 | Autosomal recessive | 3 |
| Esophageal squamous cell carcinoma, somatic | 133239 | 3 | ||
| Spinocerebellar ataxia, autosomal recessive 12 | 614322 | Autosomal recessive | 3 |
By use of shotgun genomic sequencing and isolation and analysis of transcripts mapping to a region of chromosome 16 commonly affected by allelic loss in breast cancer, Bednarek et al. (2000) identified and cloned a novel gene, the genomic structure of which spanned the entire region. They designated the gene WWOX because it encodes a 414-amino acid protein containing 2 WW domains coupled to a region with high homology to the short-chain dehydrogenase/reductase (SRD) family of enzymes. Northern blot analysis detected overexpression of a 2.2-kb WWOX transcript in breast cancer cell lines when compared to normal tissues. The highest normal expression was detected in hormonally regulated tissues such as testis, ovary, and prostate. This expression pattern and the presence of an SRD domain and specific amino acid features suggested a role for WWOX in steroid metabolism. The presence of WW domains indicated a role in protein-protein interactions.
Ried et al. (2000) independently identified this alternatively spliced gene, which they named FOR (fragile site FRA16D oxidoreductase). Alternatively spliced FOR transcripts (FOR I, FOR II, and FOR III) encode proteins which share N-terminal WW domains and differ at their C termini, with FOR III having a truncated oxidoreductase domain.
Using Western blot analysis and immunocytochemical staining, Aqeilan et al. (2007) found that mouse Wwox was expressed predominantly as a cytoplasmic protein in all tissues examined, with highest levels in prostate, bone, lung, endocrine tissues, and brain.
Chang et al. (2001) showed that the mouse Wox1 protein is an essential mediator of tumor necrosis factor-alpha-induced apoptosis. Furthermore, mouse Wox1 protein binds directly to p53 (191170), and blocking Wox1 by expression of antisense mRNA abolishes p53-mediated apoptosis in NIH 3T3 cells. The high conservation of WWOX protein between Homo sapiens and Mus musculus (93% identity) supported a similar, important role in apoptosis for human WWOX.
Bednarek et al. (2001) presented data indicating that WWOX behaves as a potent suppressor of tumor growth and suggesting that abnormalities affecting this gene at the genomic and transcriptional level may be relevant in carcinogenesis.
Chang et al. (2003) found that Jnk1 (MAPK8; 601158) inhibited Wox1-mediated apoptosis in mouse and human cell cultures. Jnk1 phosphorylated Wox1 and interacted directly with phosphorylated Wox1 in coimmunoprecipitation assays.
Bednarek et al. (2000) determined that the WWOX gene contains 9 exons.
By genomic sequence analysis, Bednarek et al. (2000) mapped the WWOX gene to chromosome 16q23.3-q24.1
Two of the most frequently observed fragile sites in humans, FRA3B (see 601153) and FRA16D, show a high frequency of breakage and colocalize with genes crossing large regions of breakage. At FRA3B, the fragile histidine triad gene (FHIT; 601153) spans more than 1 Mb, and at FRA16D the WWOX gene spans more than 750 kb. In the mouse, the common fragile site Fra14A2 and the Fhit gene are conserved in the homologous region of the genome. Krummel et al. (2002) positioned the mouse homolog of WWOX (Wox1) at band 8E1 of the mouse genome, colocalizing with Fra8E1. The sequence from this region, including introns, is highly conserved over at least a 100-kb region. This evolutionary conservation suggests that the 2 most active common fragile sites share many features and that they and their associated genes may be necessary for cell survival.
Bednarek et al. (2000) performed a mutation screen of WWOX exons in a panel of breast cancer lines, most of which were hemizygous for the 16q genomic region associated with allelic loss in breast cancer. They found no evidence of mutations, indicating that WWOX is probably not a tumor suppressor gene. However, they observed that 1 case of homozygous deletion and 2 previously described translocation breakpoints map to intronic regions of this gene. They speculated that the WWOX gene may span the region of the common fragile site FRA16D.
Ried et al. (2000) determined that FRA16D-associated deletions selectively affect the FOR gene transcripts, and 3 of 5 previously mapped translocation breakpoints in multiple myeloma are also located within the FOR gene. The authors hypothesized that FOR is therefore the principal genetic target for DNA instability at 16q23.2 and that perturbation of FOR function is likely to contribute to the biologic consequences of DNA instability at FRA16D in cancer cells.
In a mutation screen of WWOX in human cancer, Paige et al. (2001) demonstrated homozygous deletion of WWOX exons from ovarian cancer cells and 3 different tumor cell lines. They also identified an internally deleted WWOX transcript from a further primary ovarian tumor. In 3 of these samples the deletions resulted in frameshifts, and in each case the resulting WWOX transcripts lacked part, or all, of the short-chain dehydrogenase domain and the putative mitochondrial localization signal. Sequencing demonstrated several missense polymorphisms in tumor cell lines and identified a high level of single nucleotide polymorphism within the WWOX gene. The authors stated that the evidence strengthened the case for WWOX as a tumor suppressor gene in ovarian cancer and other tumor types.
Finnis et al. (2005) screened 53 cancer cell lines for deletions in the WWOX gene and detected deletions in the Co115, KM12C, and KM12SM cell lines. Homozygous deletions in these and 2 previously identified tumor cell lines were intragenic on both alleles, suggesting a distinct mutation mechanism from that causing LOH. Identical FRA16D deletions in 2 cell lines demonstrated that FRA16D DNA instability can be an early, transient event. Sequence analysis of 1 deletion implicated AT-rich repeats in FRA16D DNA instability. Another deletion was associated with de novo repetition of a 9-bp AT-rich sequence at 1 of the deletion endpoints. FRA16D-deleted cells retained cytogenetic fragile site expression, indicating that the deletions were susceptible sites for breakage rather than regions that confer fragility. Most cell lines with FRA16D homozygous deletions also had FRA3B deletions. Finnis et al. (2005) concluded that common fragile sites represent highly susceptible genomewide targets for a distinct form of mutation.
Jiang et al. (2009) analyzed chromatin modification patterns within the 6 human common fragile sites (CFSs) with the highest levels of breakage, including FRA3B and FRA16D (see 605131), and their surrounding non-fragile regions. Chromatin at most of the CFSs analyzed had significantly less histone acetylation than that of their surrounding non-fragile regions. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Chromatin at the most commonly expressed CFS, FRA3B, was more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. The authors concluded that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs may be relatively more compact than that of the NCFSs, indicating a role for chromatin conformation in genomic instability at CFSs. Jiang et al. (2009) hypothesized that lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of these regions.
Autosomal Recessive Spinocerebellar Ataxia 12
In affected members of 2 consanguineous families of Saudi Arabian and Israeli Palestinian descent, respectively, with autosomal recessive spinocerebellar ataxia-12 (SCAR12; 614322), Mallaret et al. (2014) identified 2 different homozygous missense mutations in the WWOX gene (P47T, 605131.0002 and G372R, 605131.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients had onset of generalized seizures in infancy, delayed psychomotor development with mental retardation, and cerebellar ataxia. The 2 Israeli Palestinian patients also showed spasticity. Western blot analysis of patient fibroblasts showed normal amounts of the mutant P47T protein, but in vitro functional studies showed that the mutant protein was unable to bind a PPPY-containing oligopeptide, suggesting that the mutation causes a conformational change that alters its ability to interact with normal protein motifs. None of the patients or heterozygous carriers developed cancer. No WWOX mutations were found in 189 additional unrelated ataxic patients.
Developmental and Epileptic Encephalopathy 28
In an Egyptian girl, born of consanguineous parents, with developmental and epileptic encephalopathy-28 (DEE28; 616211), Abdel-Salam et al. (2014) identified a homozygous nonsense mutation in the WWOX gene (R54X; 605131.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient had microcephaly, optic atrophy, refractory seizures, and lack of psychomotor development; she died at 16 months of age. Abdel-Salam et al. (2014) noted that the phenotype was similar to that of the Wwox-null mouse, 'lethal dwarfism and epilepsy' (lde) (Suzuki et al., 2009). The findings suggested a role for WWOX in neurodevelopment.
In 5 patients from 4 families with DEE28, Mignot et al. (2015) identified compound heterozygous deletions and/or nonsense mutations affecting the WWOX gene (see, e.g., 605131.0005-605131.0010). The deletions and mutations, which were found using a combination of chromosomal microarray analysis, direct sequencing, and whole-exome sequencing, segregated with the disorder in all families. Two sibs with a slightly less severe disorder were compound heterozygous for a deletion and a missense mutation, suggesting a possible genotype/phenotype correlation. Mignot et al. (2015) commented on the large number of deletions identified, noting that WWOX is a very large gene with a predisposition for developing deletions.
Aqeilan et al. (2007) found that Wwox-null mouse pups were obtained at the expected frequency; however, 4 of 13 Wwox-null mice developed focal lesions that appeared to be chondroid osteosarcomas along the diaphysis between age 3 days and 2.5 weeks, and all died by 4 weeks of age. Wwox +/- mice were indistinguishable from wildtype littermates, but they developed spontaneous lung papillary carcinomas as adults. These mice also developed more ethyl nitrosourea-induced lung tumors and lymphomas in comparison to wildtype littermates. Wwox +/- tumors expressed Wwox protein, suggesting that haploinsufficiency of Wwox is cancer predisposing.
Suzuki et al. (2009) described a spontaneous rat mutant, 'lethal dwarfism with epilepsy' (lde/lde), characterized by dwarfism, postnatal lethality, male hypogonadism, and a high incidence of epilepsy. Neuropathology showed extracellular vacuoles in the hippocampus and amygdala, and testes analysis showed retarded differentiation of Leydig cells and increased apoptosis of spermatocytes. Sound stimulation induced epileptic seizures in 95% of lde/lde rats, which started as wild running and sometimes progressed to tonic-clonic seizures. The locus was mapped to rat chromosome 19, and a homozygous 13-bp deletion in exon 9 was found in the Wwox gene. Western blot analysis detected Wwox proteins of 47 and 42 kD in normal testes and hippocampi, whereas both products were undetectable in the testes and hippocampi of homozygous mutant rats, indicating a functionally null mutation.
Mallaret et al. (2014) observed that Wwox-null mice developed spontaneous seizures and noise-induced seizures at around 2 weeks of age. Knockout mice also developed balance disturbances. The progression of these symptoms suggested a neurodegenerative process. These mice died from failure to thrive before age 4 weeks.
Repudi et al. (2021) found that mice with conditional deletion of Wwox in neural stem/progenitor cells were born at a mendelian ratio and presented no gross abnormalities until 2 to 3 days after birth, when they began to show global developmental delay. Furthermore. the mutant mice showed seizures, ataxia, and died prematurely. Likewise, mice with conditional deletion of Wwox in mature neurons exhibited epileptic seizures, ataxia, and premature death. Both conditional knockout mouse models phenocopied Wwox -/- mice. RNA sequencing revealed transcriptomic changes of myelination and cellular alternations in whole cortex and hippocampus of Wwox mutant mice. Moreover, Wwox mutant mice exhibited hypomyelination, reduced oligodendrocyte maturation, and impaired axonal conductivity, as neuronal Wwox promoted differentiation of oligodendrocyte progenitor cells to mature oligodendrocytes. Modeling WWOX deletion in human oligocortical spheroids also resulted in hyperexcitability and hypomyelination, supporting the critical role of WWOX in the physiologic development of myelin and the pathologic development of epilepsy.
To evaluate the potential role of the WWOX gene in esophageal squamous cell carcinomas (133239), Kuroki et al. (2002) examined 36 tumors for genetic alterations in this gene. Loss of heterozygosity (LOH) at the WWOX locus was observed in 14 tumors (39%). A tumor-specific mutation, CTG (leu) to CCG (pro) in codon 291, was found in 1 tumor, and LOH analysis showed that the other allele was missing. Kuroki et al. (2002) also detected aberrant WWOX gene transcripts with absence of exons 6 to 8 in 2 tumors, and complete absence of transcript in 1 tumor. The authors concluded that alteration and inactivation of the WWOX gene may play a role in esophageal squamous cell carcinogenesis.
In 4 sibs, born of consanguineous Saudi Arabian parents, with autosomal recessive spinocerebellar ataxia-12 (SCAR12; 614322), who were originally reported by Gribaa et al. (2007), Mallaret et al. (2014) identified a homozygous c.139C-A transversion in exon 2 of the WWOX gene, resulting in a pro47-to-thr (P47T) substitution at a highly conserved residue in the first WW domain. The pro47 residue builds up the hydrophobic core of the WW domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 130) or Exome Variant Server databases. Western blot analysis of patient fibroblasts showed normal amounts of the mutant protein, but in vitro functional studies showed that the P47T protein was unable to bind a PPPY-containing oligopeptide, suggesting that the mutation causes a conformational change that alters its ability to interact with normal protein motifs.
In 2 sibs, born of consanguineous Israeli Palestinian parents, with autosomal recessive spinocerebellar ataxia-12 (SCAR12; 614322), Mallaret et al. (2014) identified a homozygous c.1114G-C transversion in exon 9 of the WWOX gene, resulting in a gly372-to-arg (G372R) substitution at a highly conserved residue in the C-terminal part of the dehydrogenase/reductase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 137) or Exome Variant Server databases. Functional studies of the G372R variant were not performed.
In an Egyptian girl, born of consanguineous parents, with developmental and epileptic encephalopathy-28 (DEE28; 616211), Abdel-Salam et al. (2014) identified a homozygous c.160G-T transversion in exon 2 of the WWOX gene, resulting in an arg54-to-ter (R54X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. The patient developed intractable seizures at age 2 months. At age 12 months, she had microcephaly (-4.6 SD), poor growth, and lack of psychomotor development. Other features included myoclonic movements and hyperreflexia as well as optic atrophy with retinal dysfunction. Brain MRI showed supratentorial atrophy with simplified gyral pattern, hypoplasia of the hippocampus and the temporal lobe, and thin corpus callosum. She died at age 16 months. She was 1 of twins; the other twin was unaffected and heterozygous for the mutation. An older sib had died at age 3 months of a similar disorder. That sib developed seizures at age 40 days and did not follow objects or react to light, suggesting retinal degeneration.
In a girl (family 1) with developmental and epileptic encephalopathy-28 (DEE28; 616211), Mignot et al. (2015) identified compound heterozygous intragenic deletions in the WWOX gene: a 131-kb deletion encompassing exons 1 through 5, and an 82-kb deletion (605131.0006) encompassing exons 6 through 8. The deletions, which were found by chromosomal microarray analysis, segregated with the disorder in the family. Analysis of patient cells showed that the 82-kb deletion resulted in an in-frame deletion (His173_Met252del). Western blot analysis of patient cells showed complete absence of the normal 46-kD WWOX protein. The patient had onset of seizures at 2 months of age.
For discussion of the 82-kb deletion in the WWOX gene that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-28 (DEE28; 616211) by Mignot et al. (2015), see 605131.0005.
In a girl (family 2) with developmental and epileptic encephalopathy-28 (DEE28; 616211), Mignot et al. (2015) identified compound heterozygosity for a 157-kb deletion in the WWOX gene including exon 6 and a c.1005G-A transition in exon 8 of the WWOX gene, resulting in a trp335-to-ter (W335X; 605131.0008) substitution. The 157-kb deletion was predicted to result in a frameshift and premature termination (His173AlafsTer67). The mutations segregated with the disorder in the family. Western blot analysis of patient cells showed complete absence of the WWOX protein. The patient had onset of seizures at 2 months of age.
For discussion of the trp335-to-ter (W335X) mutation in the WWOX gene that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-28 (DEE28; 616211) by Mignot et al. (2015), see 605131.0007.
In 2 sibs (patients 3 and 4) with developmental and epileptic encephalopathy-28 (DEE28; 616211), Mignot et al. (2015) identified compound heterozygous mutations in the WWOX gene: a 4-bp deletion (c.45_48delGGAC) in exon 1, resulting in a frameshift and premature termination (Asp16SerfsTer63), and a c.140C-G transversion in exon 2, resulting in a pro47-to-arg (P47R; 605131.0010) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP, Exome Variant Server, and 1000 Genomes Project databases, and segregated with the disorder in the family. Functional studies of the missense mutation were not performed, but Mignot et al. (2015) noted that a different mutation affecting this codon (P47T; 605131.0002) is associated with the less severe disorder SCAR12 (614322). The patients had onset of seizures at 5 months of age.
For discussion of the pro47-to-arg (P47R) mutation in the WWOX gene that was found in compound heterozygous state in 2 patients with developmental and epileptic encephalopathy-28 (DEE28; 616211) by Mignot et al. (2015), see 605131.0009.
Abdel-Salam, G., Thoenes, M., Afifi, H. H., Korber, F., Swan, D., Bolz, H. J. 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: 12, 2014. Note: Electronic Article. [PubMed: 24456803] [Full Text: https://doi.org/10.1186/1750-1172-9-12]
Aqeilan, R. I., Trapasso, F., Hussain, S., Costinean, S., Marshall, D., Pekarsky, Y., Hagan, J. P., Zanesi, N., Kaou, M., Stein, G. S., Lian, J. B., Croce, C. M. Targeted deletion of Wwox reveals a tumor suppressor function. Proc. Nat. Acad. Sci. 104: 3949-3954, 2007. [PubMed: 17360458] [Full Text: https://doi.org/10.1073/pnas.0609783104]
Bednarek, A. K., Keck-Waggoner, C. L., Daniel, R. L., Laflin, K. J., Bergsagel, P. L., Kiguchi, K., Brenner, A. J., Aldaz, C. M. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res. 61: 8068-8073, 2001. [PubMed: 11719429]
Bednarek, A. K., Laflin, K. J., Daniel, R. L., Liao, Q., Hawkins, K. A., Aldaz, C. M. 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: 2140-2145, 2000. [PubMed: 10786676]
Chang, N.-S., Doherty, J., Ensign, A. JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J. Biol. Chem. 278: 9195-9202, 2003. [PubMed: 12514174] [Full Text: https://doi.org/10.1074/jbc.M208373200]
Chang, N.-S., Pratt, N., Heath, J., Schultz, L., Sleve, D., Carey, G. B., Zevotek, N. Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity. J. Biol. Chem. 276: 3361-3370, 2001. [PubMed: 11058590] [Full Text: https://doi.org/10.1074/jbc.M007140200]
Finnis, M., Dayan, S., Hobson, L., Chenevix-Trench, G., Friend, K., Ried, K., Venter, D., Woollatt, E., Baker, E., Richards, R. I. Common chromosomal fragile site FRA16D mutation in cancer cells. Hum. Molec. Genet. 14: 1341-1349, 2005. [PubMed: 15814586] [Full Text: https://doi.org/10.1093/hmg/ddi144]
Gribaa, M., Salih, M., Anheim, M., Lagier-Tourenne, C., H'mida, D., Drouot, N., Mohamed, A., Elmalik, S., Kabiraj, M., Al-Rayess, M., Almubarak, M., Betard, C., Goebel, H., Koenig, M. A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23. Brain 130: 1921-1928, 2007. [PubMed: 17470496] [Full Text: https://doi.org/10.1093/brain/awm078]
Jiang, Y., Lucas, I., Young, D. J., Davis, E. M., Karrison, T., Rest, J. S., Le Beau, M. M. Common fragile sites are characterized by histone hypoacetylation. Hum. Molec. Genet. 18: 4501-4512, 2009. [PubMed: 19717471] [Full Text: https://doi.org/10.1093/hmg/ddp410]
Krummel, K. A., Denison, S. R., Calhoun, E., Phillips, L. A., Smith, D. I. The common fragile site FRA16D and its associated gene WWOX are highly conserved in the mouse at Fra8E1. Genes Chromosomes Cancer 34: 154-167, 2002. [PubMed: 11979549] [Full Text: https://doi.org/10.1002/gcc.10047]
Kuroki, T., Trapasso, F., Shiraishi, T., Alder, H., Mimori, K., Mori, M., Croce, C. M. Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. Cancer Res. 62: 2258-2260, 2002. [PubMed: 11956080]
Mallaret, M., Synofzik, M., Lee, J., Sagum, C. A., Mahajnah, M., Sharkia, R., Drouot, N., Renaud, M., Klein, F. A. C., Anheim, M., Tranchant, C., Mignot, C., Mandel, J.-L., Bedford, M., Bauer, P., Salih, M. A., Schule, R., Schols, L., Aldaz, C. M., Koenig, M. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 137: 411-419, 2014. [PubMed: 24369382] [Full Text: https://doi.org/10.1093/brain/awt338]
Mignot, C., Lambert, L., Pasquier, L., Bienvenu, T., Delahaye-Duriez, A., Keren, B., Lefranc, J., Saunier, A., Allou, L., Roth, V., Valduga, M., Moustaine, A., and 14 others. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J. Med. Genet. 52: 61-70, 2015. [PubMed: 25411445] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102748]
Paige, A. J. W., Taylor, K. J., Taylor, C., Hillier, S. G., Farrington, S., Scott, D., Porteous, D. J., Smyth, J. F., Gabra, H., Watson, J. E. V. WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc. Nat. Acad. Sci. 98: 11417-11422, 2001. [PubMed: 11572989] [Full Text: https://doi.org/10.1073/pnas.191175898]
Repudi, S., Steinberg, D. J., Elazar, N., Breton, V. L., Aquilino, M. S., Saleem, A., Abu-Swai, S., Vainshtein, A., Eshed-Eisenbach, Y., Vijayaragavan, B., Behar, O., Hanna, J. J., Peles, E., Carlen, P. L., Aqeilan, R. I. Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects. Brain 144: 3061-3077, 2021. [PubMed: 33914858] [Full Text: https://doi.org/10.1093/brain/awab174]
Ried, K., Finnis, M., Hobson, L., Mangelsdorf, M., Dayan, S., Nancarrow, J. K., Woollatt, E., Kremmidiotis, G., Gardner, A., Venter, D., Baker, E., Richards, R. I. Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum. Molec. Genet. 9: 1651-1663, 2000. [PubMed: 10861292] [Full Text: https://doi.org/10.1093/hmg/9.11.1651]
Suzuki, H., Katayama, K., Takenaka, M., Amakasu, K., Saito, K., Suzuki, K. A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with lethal dwarfism and epilepsy. Genes Brain Behav. 8: 650-660, 2009. [PubMed: 19500159] [Full Text: https://doi.org/10.1111/j.1601-183X.2009.00502.x]