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dc.contributor.authorMalik, Sajid
dc.contributor.authorPercin, Ferda E.
dc.contributor.authorBornholdt, Dorothea
dc.contributor.authorAlbrecht, Beate
dc.contributor.authorPercesepe, Antonio
dc.contributor.authorKoch, Manuela C.
dc.contributor.authorLandi, Antonio
dc.contributor.authorFritz, Barbara
dc.contributor.authorKhan, Rizwan
dc.contributor.authorMumtaz, Sara
dc.contributor.authorAkarsu, Nurten A.
dc.contributor.authorGrzeschik, Karl-Heinz
dc.date.accessioned2019-12-10T11:33:00Z
dc.date.available2019-12-10T11:33:00Z
dc.date.issued2014
dc.identifier.issn0002-9297
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2014.10.012
dc.identifier.urihttp://hdl.handle.net/11655/16078
dc.description.abstractMesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.
dc.language.isoen
dc.publisherCell Press
dc.relation.isversionof10.1016/j.ajhg.2014.10.012
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGenetics & Heredity
dc.titleMutations Affecting The Bhlha9 Dna-Binding Domain Cause Mssd, Mesoaxial Synostotic Syndactyly With Phalangeal Reduction, Malik-Percin Type
dc.typeinfo:eu-repo/semantics/article
dc.relation.journalAmerican Journal Of Human Genetics
dc.contributor.departmentTıbbi Genetik
dc.identifier.volume95
dc.identifier.issue6
dc.identifier.startpage649
dc.identifier.endpage659
dc.description.indexWoS
dc.description.indexScopus


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