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WIREs Dev Biol
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The molecular basis of human congenital limb malformations

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Abstract This review focuses predominantly on the human congenital malformations caused by alterations affecting the morphoregulatory gene networks that control early limb bud patterning and outgrowth. Limb defects are among the most frequent congenital malformations in humans that are caused by genetic mutations or teratogenic effects resulting either in abnormal, loss of, or additional skeletal elements. Spontaneous and engineered mouse models have been used to identify and study the molecular alterations and disrupted gene networks that underlie human congenital limb malformations. More recently, mouse genetics has begun to reveal the alterations that affect the often‐large cis‐regulatory landscapes that control gene expression in limb buds and cause devastating effects on limb bud development. These findings have paved the way to identifying mutations in cis‐regulatory regions as causal to an increasing number of congenital limb malformations in humans. In these cases, no mutations in the coding region of a presumed candidate were previously detected. This review highlights how the current understanding of the molecular gene networks and interactions that control mouse limb bud development provides insight into the etiology of human congenital limb malformations. WIREs Dev Biol 2012 doi: 10.1002/wdev.59 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Vertebrate Organogenesis > Musculoskeletal and Vascular Birth Defects > Organ Anomalies

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Human congenital limb malformations. (a) Human arm and leg skeletons. The stylopod (humerus/femur) indicated in red is the most proximal limb skeletal element. The ulna/radius (arm) or tibia/fibula (leg) form the zeugopod (green). The distal‐most part of the limb is the autopod (hand/foot, blue) and consists of carpals or tarsals, metacarpals or metatarsals, and phalanges. The drawing of limb skeletons are from Ref 16. (b) Illustrations of the most common types of human congenital limb malformations (see Table 1 for terms). These illustrations are provided and reprinted with permission from D. Hueskes (University Hospital Basel; phocomelia, hemimelia, acheiria, hypodactyly, and syndactyly), the National Human Genome Research Institute (http://www.genome.gov/; adactyly). (Reprinted with permission from Ref 17. Copyright 2010 African Health Sciences [sirenomelia]; Reprinted with permission from Ref 18 Copryright 2008 BioMed Central Ltd. [preaxial polydactyly]; Reprinted with permission from Ref 19. Copyright 2003 Oxford University Press [ectrodactyly]; Reprinted with permission from Ref 20. Copyright 2008 Nature Publishing Group [postaxial polydactyly])

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Improving disabilities caused by congenital limb malformations. (a)–(d) Surgical correction of foot and hand polydactylies ((a), (c): before; (b), (d): after surgical correction). (Reprinted with permission from Ref 102. Copyright 2007 Elsevier Limited; Reprinted with permission from Ref 103. Copyright 2011 Elsevier Limited). (e)–(h) Ectrodactyly (e) and distal truncations (g), (h) are compensated by custom‐made prostheses (f), (g), (h). (Reprinted with permission from Ref 104. Copyright 2008 Elsevier Limited [panels (e and f)]). A first prosthesis enabled a toddler to learn walking (g) and these were replaced by new prostheses during growth (h); panels (g), (h) reprinted with permission from D. Hueskes. (i), (j) The sculpture ‘Alison Lapper pregnant’ by Marc Quinn was on public display in Trafalgar Square, London from 2005 to 2007 and caused a large debate on the society's perception of people with disabilities (panels (i) and (j) reprinted with permission from http://lunettesrouges.blog.lemonde.fr and D. Ghose, respectively).

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Comparison of human and mouse limb skeletal phenotypes caused by mutations affecting the same gene. X‐ray images of human autopods (a), (c), (e), (h), (j), (l) are compared to skeletal preparations of mouse limbs (b), (d), (f), (g), (i), (m), (k). (a)–(d) Mutations disrupting SHH expression in limb buds. (a) Acheiropody is caused by a cis‐regulatory mutation within the LMBR1 locus that results in autopod loss. (Reprinted with permission from Ref 48. Copyright 2001 Elsevier Limited). (b) Targeted Shh loss‐of‐function mutation in the mouse (Source: P. Schlenker). Only one digit with three phalanges is formed. The homologous skeletal regions are indicated by brackets in panels (a) and (b). (c), (d) Pre‐axial polydactylies caused by mutations in the ZRS. (Reprinted with permission from Ref 36. Copyright 2003 John Wiley and Sons; Box 2). (e)–(g) Cis‐regulatory mutations altering the GREM1‐FMN1 landscape cause hyposyndactylies. (e) A deletion in the GREM1‐FMN1 landscape of a human patient. (Reprinted with permission from Ref 43. Copyright 2010 BMJ Publishing Group Ltd). (f), (g) The mouse Fmn1Δ10‐24 and Fmn1Δ9 alleles disrupt the Grem1‐Fmn1 cis‐regulatory landscape. (h), (i) Hypodactylies caused by WNT7A mutations. (Reprinted with permission from Ref 50. Copyright 2011 John Wiley and Sons). Note the more severe limb phenotype in humans than in mice (panel (i), left limb). The limb phenotypes of the Wnt7a deficiency in mice are enhanced by additional inactivation of the WNT co‐receptor Lrp6 (panel (i), right limb). (Reprinted with permission from Ref 51. Copyright 2005 John Wiley and Sons). (j), (k) SPD1 is caused by microdeletion of HOXD9‐13 and cis‐regulatory regions in a human patient (j) and deletion of Hoxd11‐13 in the mouse. (Reprinted with permission from Ref 41. Copyright 2002 Elsevier Limited [panel (j)]; Reprinted with permission from Ref 52. Copyright 1996 Nature Publishing Group [panel (k)]). (l), (m) Ectrodactyly caused by mutations in the DLX5/DLX6 locus. (Reprinted with permission from Ref 4. Copyright 2001 John Wiley and Sons; Reprinted with permission from Ref 53. Copyright 2002 John Wiley and Sons)

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Schematic overview of the major signaling pathways active in limb buds. (a) SHH signal transduction in the presence (on) and absence (off) of ligand. GLIFL: full‐length GLI protein. GLIA: the activated full‐length protein functioning as a transcriptional activator. (b) FGF signal transduction. (c) BMP signal transduction. (d) Canonical WNT pathway signal transduction. CTNNB1: formerly β‐catenin. TCF: T cell factor/lymphoid enhancer factor family of transcription factors (TCF/LEF).

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Gene interactions during limb bud development. (a) Scanning electron microscopy of a mouse embryo. The enlarged forelimb bud indicates the two main limb bud axes and the apical ectodermal ridge (AER). (b) Initiation: major molecular interactions controlling AER induction and initiation of limb bud outgrowth. (c) Activation of SHH signaling: the interactions controlling activation of Shh expression in the posterior mesenchyme are shown. (d) Outgrowth and patterning: the interlinked feedback loops operating between mesenchyme and AER control patterning and proliferation of the limb bud mesenchymal progenitors. Color codes indicate the following pathways: BMP (orange), FGF (blue), retinoic acid (RA; green), SHH (red), transcription factors (purple), and WNT (brown). The AER is located at the distal tip of the limb bud and indicated by dark gray shading.

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Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
Vertebrate Organogenesis > Musculoskeletal and Vascular
Birth Defects > Organ Anomalies