Dissecting the genetic complexity of human 6p deletion syndromes by using a region-specific, phenotype-driven mouse screen

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dc.contributor.authorBogani, Debora
dc.contributor.authorWilloughby, Catherine
dc.contributor.authorDavies, Jennifer
dc.contributor.authorKaur, Kulvinder
dc.contributor.authorMirza, Ghazala
dc.contributor.authorPaudyal, Anju
dc.contributor.authorHaines, Heather
dc.contributor.authorMcKeone, Richard
dc.contributor.authorCadman, Matthew
dc.contributor.authorPieles, Guido
dc.contributor.authorSchneider, Jurgen E
dc.contributor.authorBattacharya, Shoumo
dc.contributor.authorHardy, Andrea
dc.contributor.authorNolan, Patrick
dc.contributor.authorTripodis, Nikos
dc.contributor.authorDepew, Michael J
dc.contributor.authorChandrasekara, Ramya
dc.contributor.authorDuncan, Gimara
dc.contributor.authorSharpe, Paul T
dc.contributor.authorGreenfield, Andy
dc.contributor.authorDenny, Paul
dc.contributor.authorBrown, Steve D M
dc.contributor.authorRagoussis, Jiannis
dc.contributor.authorArkell, Ruth
dc.date.accessioned2015-12-10T22:23:18Z
dc.date.issued2005
dc.date.updated2015-12-09T09:06:37Z
dc.description.abstractMonosomy of the human chromosome 6p terminal region results in a variety of congenital malformations that include brain, craniofacial, and organogenesis abnormalities. To examine the genetic basis of these phenotypes, we have carried out an unbiased functional analysis of the syntenic region of the mouse genome (proximal Mmu13). A genetic screen for recessive mutations in this region recovered thirteen lines with phenotypes relevant to a variety of clinical conditions. These include two loci that cause holoprosencephaly, two that underlie anophthalmia, one of which also contributes to other craniofacial abnormalities such as microcephaly, agnathia, and palatogenesis defects, and one locus responsible for developmental heart and kidney defects. Analysis of heterozygous carriers of these mutations shows that a high proportion of these loci manifest with behavioral activity and sensorimotor deficits in the heterozygous state. This finding argues for the systematic, reciprocal phenotypic assessment of dominant and recessive mouse mutants. In addition to providing a resource of single gene mutants that model 6p-associated disorders, the work reveals unsuspected genetic complexity at this region. In particular, many of the phenotypes associated with 6p deletions can be elicited by mutation in one of a number of genes. This finding implies that phenotypes associated with contiguous gene deletion syndromes can result not only from dosage sensitivity of one gene in the region but also from the combined effect of monosomy for multiple genes that function within the same biological process.
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/1885/52722
dc.publisherNational Academy of Sciences (USA)
dc.sourcePNAS - Proceedings of the National Academy of Sciences of the United States of America
dc.subjectKeywords: animal experiment; animal model; anophthalmia; article; brain malformation; chromosome 6p deletion syndrome; chromosome deletion; congenital heart malformation; craniofacial malformation; embryo; female; gene deletion; gene locus; gene mutation; genetic a Anophthalmia; ENU mutagenesis; Holoprosencephaly
dc.titleDissecting the genetic complexity of human 6p deletion syndromes by using a region-specific, phenotype-driven mouse screen
dc.typeJournal article
local.bibliographicCitation.issue35
local.bibliographicCitation.lastpage12482
local.bibliographicCitation.startpage12477
local.contributor.affiliationBogani, Debora, Medical Research Council
local.contributor.affiliationWilloughby, Catherine, Medical Research Council
local.contributor.affiliationDavies, Jennifer, Medical Research Council
local.contributor.affiliationKaur, Kulvinder, University of Oxford
local.contributor.affiliationMirza, Ghazala, University of Oxford
local.contributor.affiliationPaudyal, Anju, Medical Research Council
local.contributor.affiliationHaines, Heather, Medical Research Council
local.contributor.affiliationMcKeone, Richard , Medical Research Council
local.contributor.affiliationCadman, Matthew, Medical Research Council
local.contributor.affiliationPieles, Guido, University of Oxford
local.contributor.affiliationSchneider, Jurgen E, University of Oxford
local.contributor.affiliationBattacharya, Shoumo, University of Oxford
local.contributor.affiliationHardy, Andrea, Medical Research Council
local.contributor.affiliationNolan, Patrick, Medical Research Council
local.contributor.affiliationTripodis, Nikos, King's College London
local.contributor.affiliationDepew, Michael J, King's College London
local.contributor.affiliationChandrasekara, Ramya, King's College London
local.contributor.affiliationDuncan, Gimara, King's College London
local.contributor.affiliationSharpe, Paul T, King's College London
local.contributor.affiliationGreenfield, Andy, Medical Research Council
local.contributor.affiliationDenny, Paul, Medical Research Council
local.contributor.affiliationBrown, Steve D M, Medical Research Council
local.contributor.affiliationRagoussis, Jiannis, University of Oxford
local.contributor.affiliationArkell, Ruth, College of Medicine, Biology and Environment, ANU
local.contributor.authoremailu4350791@anu.edu.au
local.contributor.authoruidArkell, Ruth, u4350791
local.description.embargo2037-12-31
local.description.notesImported from ARIES
local.identifier.absfor060403 - Developmental Genetics (incl. Sex Determination)
local.identifier.ariespublicationu9204316xPUB253
local.identifier.citationvolume102
local.identifier.doi10.1073/pnas.0500584102
local.identifier.scopusID2-s2.0-24644469582
local.identifier.uidSubmittedByu9204316
local.type.statusPublished Version

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