Disorganization is a completely dominant gain-of-function mouse mutation causing sporadic developmental defects

Crosby, Jeffrey L.; Varnum, Don S.; Washburn, Linda L.; Nadeau, Joseph H.

doi:10.1016/0925-4773(92)90074-t

Cited by 26 publications

(19 citation statements)

References 33 publications

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“…This is suggested by experiments in which mice trisomic for the Ds chromosome were created, with wt/wt/Ds manifesting anomalies seen in Ds, and not seen in wt/wt/wt control mice [Crosby et al, 1992]. This shows that a second wt copy of the Ds allele cannot rescue the Ds phenotype, arguing against a loss-of-function mutation and suggesting the gain-of-function mechanism.…”

Section: Disorganization Geneticsmentioning

confidence: 83%

Disorganization in mice and humans

Robin

Nadeau

2001

Am. J. Med. Genet.

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Disorganization (Ds) is an autosomal dominant mouse mutant that produces a remarkable array of birth defects. So variable is the phenotype that no two mice appear identical. Ds also has markedly reduced penetrance, with 85-99% of Ds mice having no apparent anomalies. Paired structures are often affected, but always asymmetrically. Although the Ds gene has yet to be identified, it is thought that Ds is a gain-of-function mutation, and that Ds malformations are thought to arise through a two-hit mechanism. Unlike the two-hit model that has been used to describe the development of retinoblastoma, the "second hit" for Ds is thought not to arise in the other Ds allele. Although there is a long list of anomalies seen in Ds mice, two stand out as most characteristic: hamartomatous skin papillae, and mirror-image limb duplications. Through the observation of these unusual anomalies in human cases, the possibility of a human homologue of Ds was suggested. However, in reviewing types of anomalies seen in Ds mice, it is apparent that cases with these unusual defects represent only one end of the spectrum of the Ds phenotype. Ds may be the genetic basis for more usual and seemingly sporadic human birth defects as well.

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Section: Disorganization Geneticsmentioning

confidence: 83%

Disorganization in mice and humans

Robin

Nadeau

2001

Am. J. Med. Genet.

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“…Ds mice share many malformations [38–41] in common with those of Polypodia , yet there are differences. Ds mice do not exhibit prenatal lethality, either as heterozygotes or homozygotes [40]. It will be interesting to compare the molecular pathways affected in both mutants.…”

Section: Discussionmentioning

confidence: 99%

A Novel Intergenic ETnII-β Insertion Mutation Causes Multiple Malformations in Polypodia Mice

et al. 2013

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Mouse early transposon insertions are responsible for ∼10% of spontaneous mutant phenotypes. We previously reported the phenotypes and genetic mapping of Polypodia, (Ppd), a spontaneous, X-linked dominant mutation with profound effects on body plan morphogenesis. Our new data shows that mutant mice are not born in expected Mendelian ratios secondary to loss after E9.5. In addition, we refined the Ppd genetic interval and discovered a novel ETnII-β early transposon insertion between the genes for Dusp9 and Pnck. The ETn inserted 1.6 kb downstream and antisense to Dusp9 and does not disrupt polyadenylation or splicing of either gene. Knock-in mice engineered to carry the ETn display Ppd characteristic ectopic caudal limb phenotypes, showing that the ETn insertion is the Ppd molecular lesion. Early transposons are actively expressed in the early blastocyst. To explore the consequences of the ETn on the genomic landscape at an early stage of development, we compared interval gene expression between wild-type and mutant ES cells. Mutant ES cell expression analysis revealed marked upregulation of Dusp9 mRNA and protein expression. Evaluation of the 5′ LTR CpG methylation state in adult mice revealed no correlation with the occurrence or severity of Ppd phenotypes at birth. Thus, the broad range of phenotypes observed in this mutant is secondary to a novel intergenic ETn insertion whose effects include dysregulation of nearby interval gene expression at early stages of development.

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“…Two particularly striking anomalies are single limb mirror-image duplications and hamartomatous skin papillae. Unilateral microphthalmia, unilateral anotia, and asymmetric cerebral hemispheres are also found [Hummel, 1958[Hummel, , 1959Crosby et al, 1992Crosby et al, , 1993. It has been suggested that some patients with unusual anomalies [Gebbia et al, 1997;.…”

Section: Asymmetry In Animalsmentioning

confidence: 99%

Asymmetry: Molecular, biologic, embryopathic, and clinical perspectives

Cohen

2001

Am. J. Med. Genet.

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This overview of asymmetry addresses the following topics: chiral molecules; asymmetric signaling molecules, including N-cadherin, Shh, Fgf8, lefty1, lefty2, nodal, Pitx2, activin betaB, activin receptor IIA, and cSnR; situs abnormalities; asymmetric cell division; laterality in humans and animals; behavioral asymmetry in humans and animals; asymmetric embryopathies, including Tessier-type "clefts"; hemiasymmetries such as hemihyperplasia, hemihypoplasia, and hemiatrophy; asymmetric vascular syndromes, including Klippel-Trenaunay and Sturge-Weber syndromes; plagiocephaly of the synostotic and deformational types; somatic mosaicism, including a discussion of McCune-Albright syndrome, fibrous dysplasia, GNAS1 mutations, and Proteus syndrome.

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Disorganization is a completely dominant gain-of-function mouse mutation causing sporadic developmental defects

Cited by 26 publications

References 33 publications

Disorganization in mice and humans

Disorganization in mice and humans

A Novel Intergenic ETnII-β Insertion Mutation Causes Multiple Malformations in Polypodia Mice

Asymmetry: Molecular, biologic, embryopathic, and clinical perspectives

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