Cis-Regulatory Enhancer Mutations are a Cause of Human Limb Malformations

  • Julia E. VanderMeer
  • Nadav AhituvEmail author


Congenital limb malformations are the second most common class of human birth defects and can be caused both by environmental and genetic factors. While it is known that some limb malformations are the result of coding mutations that disrupt genes, identifying the causal mutation in a patient with an isolated limb malformation is often difficult. This may be due in part to the growing number of cases with isolated limb malformations that are shown to be the result of nucleotide changes in gene regulatory elements. These regulatory mutations affect gene expression in the developing limb and can cause dramatic changes to patterning, leading to congenital limb malformations. In this chapter, we will review characterized gene regulatory mutations leading to human limb malformations and also provide evidence that additional limb enhancers could be the cause of other human limb malformations.


Limb Sonic hedgehog ZPA ZRS BMP2 SOX9 Polydactyly Brachydactyly 



Apical ectodermal ridge


Anterior-posterior [axis]


Brachydactyly type A2


Bone morphogenic protein


Bone morphogenic protein 2


Base pairs


Chromatin immunoprecipitation


Chromatin immunoprecipitation followed by deep sequencing


Distal-less homeobox 5 and 6


Dorsal-ventral [axis]


Fibroblast growth factor 4


Fibroblast growth factor 8


Fibroblast growth factor 10


GLI family zinc finger 3


Gremlin 1






Limb region 1


Proximal-distal [axis]


Paired-like homeodomain 1


Preaxial polydactyly


Parathyroid hormone-like hormone


Split hand-foot malformation


Sonic hedgehog


SRY-box containing gene 9


T-box 4


Transcription factor


Triphalangeal thumb


Triphalangeal thumb polysyndactyly


Zone of polarizing activity


ZPA regulatory sequence


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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Bioengineering and Therapeutic Sciences, Institute for Human GeneticsUniversity of California San FranciscoSan FranciscoUSA

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