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Missense-Mutationen in Transkriptionsfaktoren

Einschätzung und funktionelle Charakterisierung pathogener Transkriptionsfaktormutationen

Missense mutations in transcription factors

Assessment and functional characterization of pathogenic transcription factor mutations


Transkriptionsfaktoren sind entscheidende Regulatoren der Embryonalentwicklung, da sie die Genexpression in jeder Zelle kontrollieren. Mutationen in Transkriptionsfaktoren liegen häufig angeborenen Entwicklungsdefekten zugrunde, jedoch ist die funktionelle Einschätzung der Pathogenität einzelner Transkriptionsfaktorvarianten anspruchsvoll, da die molekulare Funktionsweise von Transkriptionsfaktoren nicht vollkommen verstanden ist. Besonders Gain-of-Function-Mutationen führen häufig zu neuen, unerwarteten Phänotypen, deren funktionelle Charakterisierung eine Herausforderung darstellt. Die im letzten Jahrzehnt entwickelte ChIP-seq-Technologie ermöglicht es, die molekularen Mechanismen zu unterscheiden, welche Transkriptionsfaktor-assoziierten Krankheiten zugrunde liegen. Dieser Artikel fasst die molekularen Pathomechanismen diverser Transkriptionsfaktormutationen zusammen und versucht einen molekularbiologischen Rahmen für die Bewertung neuer Transkriptionsfaktormutationen zu geben.


Transcription factors (TF) are key regulators that control the cell-type-specific gene expression in each individual cell and are crucial for the coordination of embryonic development. Mutations in TFs frequently underlie heritable developmental defects; however, the functional characterization of a variant TF is challenging, since the exact molecular mechanisms by which TFs exert their function are not fully understood. In particular, gain-of-function mutations can lead to novel phenotypes that are difficult to characterize functionally. Recent technological advances, in particular ChIP-seq, have enabled experimental approaches that can distinguish between distinct molecular mechanisms underlying TF-associated diseases. This article reviews the molecular pathomechanisms underlying various TF mutations and proposes approaches to previously unknown TF mutations.

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Abb. 1


  1. 1

    Albrecht AN, Kornak U, Böddrich A et al (2004) A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. Hum Mol Genet 13:2351–2359

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Basson CT, Huang T, Lin RC et al (1999) Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci USA 96:2919–2924

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. 3

    Brison N, Debeer P, Tylzanowski P (2014) Joining the fingers: a HOXD13 story. Dev Dyn 243:37–48

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Cantor AB, Iwasaki H, Arinobu Y et al (2008) Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage. J Exp Med 205:611–624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. 5

    Chlon TM, Crispino JD (2012) Combinatorial regulation of tissue specification by GATA and FOG factors. Development 139:3905–3916

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. 6

    Chlon TM, Doré LC, Crispino JD (2012) Cofactor-mediated restriction of GATA-1 chromatin occupancy coordinates lineage-specific gene expression. Mol Cell 47:608–621

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. 7

    Ciovacco WA, Raskind WH, Kacena MA (2008) Human phenotypes associated with GATA-1 mutations. Gene 427:1–6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 8

    El GV, Legeai-Mallet L, Benoist-Lasselin C et al (2001) Mutations in the basic domain and the loop–helix II junction of TWIST abolish DNA binding in Saethre–Chotzen syndrome. FEBS Lett 492:112–118

    Article  Google Scholar 

  9. 9

    Frietze S, Wang R, Yao L et al (2012) Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3. Genome Biol 13:R52

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. 10

    Fujiwara Y, Browne CP, Cunniff K et al (1996) Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci 93:12355–12358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. 11

    Gerstein MB, Kundaje A, Hariharan M et al (2012) Architecture of the human regulatory network derived from ENCODE data. Nature 489:91–100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. 12

    He A, Kong SW, Ma Q et al (2011) Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci 108:5632–5637

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. 13

    Herskowitz I (1987) Functional inactivation of genes by dominant negative mutations. Nature 329:219–222

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Ibrahim DM, Hansen P, Rodelsperger C et al (2013) Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations. Genome Res 23:2091–2102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. 15

    Infante CR, Park S, Mihala A et al (2012) Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements. Dev Biol:1–11

  16. 16

    Lesluyes T, Johnson J, Machanick P et al (2014) Differential motif enrichment analysis of paired ChIP-seq experiments. BMC Genomics 15:752

    Article  PubMed Central  PubMed  Google Scholar 

  17. 17

    Li QY, Newbury-Ecob RA, Terrett JA et al (1997) Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 15:21–29

    Article  PubMed  Google Scholar 

  18. 18

    Orlando V (2000) Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biomed Sci 25:99–104

  19. 19

    Park PJ (2009) ChIP-seq: advantages and challenges of a maturing technology. Nat Rev Genet 10:669–680

  20. 20

    Robertson G, Hirst M, Bainbridge M et al (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4:651–657

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Saadi I, Kuburas A, Engle JJ et al (2003) dominant negative dimerization of a mutant homeodomain protein in Axenfeld-Rieger syndrome. Mol Cell Biol 23:1968–1982

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. 22

    Saadi I, Semina EV, Amendt BA et al (2001) Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034–23041

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Shamseldin HE, Faden MA, Alashram W et al (2012) Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. J Med Genet 49:16–20

    Article  PubMed  Google Scholar 

  24. 24

    Spitz F, Furlong EEM (2012) Transcription factors: from enhancer binding to developmental control. Nat Rev Genet 13:613–626

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Stoltenburg R, Reinemann C, Strehlitz B (2007) SELEX—a (r)evolutionary method to generate high-affinity nucleic acid ligands. Biomol Eng 24:381–403

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Wang J, Zhuang J, Iyer S et al (2012) Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res 22:1798–1812

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. 27

    Whitfield TW, Wang J, Collins PJ et al (2012) Functional analysis of transcription factor binding sites in human promoters. Genome Biol 13:R50

    Article  PubMed Central  PubMed  Google Scholar 

  28. 28

    Wilkie AO, Tang Z, Elanko N et al (2000) Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nat Genet 24:387–390

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Zhao X, Sun M, Zhao J et al (2007) Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome. Am J Hum Genet 80:361–371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Correspondence to Daniel Murad Ibrahim.

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Daniel Murad Ibrahim gibt an, dass kein Interessenkonflikt besteht.

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Ibrahim, D. Missense-Mutationen in Transkriptionsfaktoren. medgen 27, 1–6 (2015).

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  • Transkriptionsfaktor
  • Genregulation
  • Gain-of-Function-Mutation
  • Punktmutation
  • Missense-Mutation


  • Transcription factor
  • Gene regulation
  • Gain-of-function mutation
  • Point mutation
  • Missense mutation