Abstract
The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.
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References
Riddle RD, Johnson RL, Laufer E, Tabin C : Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993; 75: 1401–1416.
Heus HC, Hing A, van Baren MJ et al: A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36. Genomics 1999; 57: 342–351.
Heutink P, Zguricas J, van Oosterhout L et al: The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nat Genet 1994; 6: 287–292.
Hing AV, Helms C, Slaugh R et al: Linkage of preaxial polydactyly type 2 to 7q36. Am J Med Genet 1995; 58: 128–135.
Tsukurov O, Boehmer A, Flynn J et al: A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nat Genet 1994; 6: 282–286.
Zguricas J, Heus H, Morales-Peralta E et al: Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36. J Med Genet 1999; 36: 32–40.
VanderMeer JE, Ahituv N : cis-regulatory mutations are a genetic cause of human limb malformations. Dev Dyn 2011; 240: 920–930.
Albuisson J, Isidor B, Giraud M et al: Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly. Clin Genet 2011; 79: 371–377.
Li H, Wang CY, Wang JX et al: Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly. Eur J Hum Genet 2009; 17: 604–610.
Chiang C, Swan RZ, Grachtchouk M et al: Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol 1999; 205: 1–9.
St-Jacques B, Dassule HR, Karavanova I et al: Sonic hedgehog signaling is essential for hair development. Curr Biol 1998; 8: 1058–1068.
Wang LC, Liu ZY, Gambardella L et al: Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration. J Invest Dermatol 2000; 114: 901–908.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR : Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Ovcharenko I, Stubbs L, Loots GG : Interpreting mammalian evolution using Fugu genome comparisons. Genomics 2004; 84: 890–895.
Fujioka H, Ariga T, Horiuchi K et al: Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I. Clin Genet 2005; 67: 429–433.
Radhakrishna U, Bornholdt D, Scott HS et al: The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. Am J Hum Genet 1999; 65: 645–655.
Biesecker LG, Johnston J : Syndromic and non-syndromic GLI3 phenotypes. Clin Genet 2005; 68: 284, author reply 285.
Kroisel PM, Petek E, Wagner K : Phenotype of five patients with Greig syndrome and microdeletion of 7p13. Am J Med Genet 2001; 102: 243–249.
Farooq M, Troelsen JT, Boyd M et al: Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS. Eur J Hum Genet 2010; 18: 733–736.
Epstein DJ, McMahon AP, Joyner AL : Regionalization of Sonic hedgehog transcription along the anteroposterior axis of the mouse central nervous system is regulated by Hnf3-dependent and -independent mechanisms. Development 1999; 126: 281–292.
Jeong Y, El-Jaick K, Roessler E, Muenke M, Epstein DJ : A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development 2006; 133: 761–772.
Sagai T, Amano T, Tamura M, Mizushina Y, Sumiyama K, Shiroishi T : A cluster of three long-range enhancers directs regional Shh expression in the epithelial linings. Development 2009; 136: 1665–1674.
Amano T, Sagai T, Tanabe H, Mizushina Y, Nakazawa H, Shiroishi T : Chromosomal dynamics at the Shh locus: limb bud-specific differential regulation of competence and active transcription. Dev Cell 2009; 16: 47–57.
Galli A, Robay D, Osterwalder M et al: Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet 2010; 6: e1000901.
Lettice LA, Williamson I, Wiltshire JH et al: Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev Cell 2012; 22: 459–467.
Gotea V, Visel A, Westlund JM, Nobrega MA, Pennacchio LA, Ovcharenko I : Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers. Genome Res 2010; 20: 565–577.
Zhang Y, Rath N, Hannenhalli S et al: GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development 2007; 134: 189–198.
Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M : The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. Embo J 1997; 16: 5687–5696.
Shiojima I, Komuro I, Oka T et al: Context-dependent transcriptional cooperation mediated by cardiac transcription factors Csx/Nkx-2.5 and GATA-4. J Biol Chem 1999; 274: 8231–8239.
Molkentin JD, Antos C, Mercer B, Taigen T, Miano JM, Olson EN : Direct activation of a GATA6 cardiac enhancer by Nkx2.5: evidence for a reinforcing regulatory network of Nkx2.5 and GATA transcription factors in the developing heart. Dev Biol 2000; 217: 301–309.
Liu C, Glasser SW, Wan H, Whitsett JA : GATA-6 and thyroid transcription factor-1 directly interact and regulate surfactant protein-C gene expression. J Biol Chem 2002; 277: 4519–4525.
Kozhemyakina E, Ionescu A, Lassar AB : GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet 2014; 10: e1004072.
Chen Y, Bates DL, Dey R et al: DNA binding by GATA transcription factor suggests mechanisms of DNA looping and long-range gene regulation. Cell Rep 2012; 2: 1197–1206.
Suzuki K, Yamaguchi Y, Villacorte M et al: Embryonic hair follicle fate change by augmented beta-catenin through Shh and Bmp signaling. Development 2009; 136: 367–372.
Ellis T, Smyth I, Riley E et al: Overexpression of Sonic Hedgehog suppresses embryonic hair follicle morphogenesis. Dev Biol 2003; 263: 203–215.
Kurek D, Garinis GA, van Doorninck JH, van der Wees J, Grosveld FG : Transcriptome and phenotypic analysis reveals Gata3-dependent signalling pathways in murine hair follicles. Development 2007; 134: 261–272.
Acknowledgements
We gratefully thank the cell culture platform of the Center of Biology-Pathology, Lille University Hospital (France) for their technical assistance in cell culturing and transfection experiments. This work was supported by funds from Lille University Hospital (France).
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Petit, F., Jourdain, AS., Holder-Espinasse, M. et al. The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis. Eur J Hum Genet 24, 37–43 (2016). https://doi.org/10.1038/ejhg.2015.53
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DOI: https://doi.org/10.1038/ejhg.2015.53
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