Abstract
PITX1 is a bicoid-related homeodomain transcription factor implicated in vertebrate hindlimb development. Recently, mutations in PITX1 have been associated with autosomal-dominant clubfoot. In addition, one affected individual showed a polydactyly and right-sided tibial hemimelia. We now report on PITX1 deletions in two fetuses with a high-degree polydactyly, that is, mirror-image polydactyly. Analysis of DNA from additional individuals with isolated lower-limb malformations and higher-degree polydactyly identified a third individual with long-bone deficiency and preaxial polydactyly harboring a heterozygous 35 bp deletion in PITX1. The findings demonstrate that mutations in PITX1 can cause a broad spectrum of isolated lower-limb malformations including clubfoot, deficiency of long bones, and mirror-image polydactyly.
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References
Kornak U, Mundlos S : Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 2003; 73: 447–474.
Stricker S, Mundlos S : Mechanisms of digit formation: human malformation syndromes tell the story. Dev Dyn 2011; 240: 990–1004.
Stevenson RE, Judith G H : Human Malformations and Related Anomalies. New York: Oxford University Press, 2005.
Marino-Enriquez A, Lapunzina P, Omenaca F, Morales C, Rodriguez JI : Laurin-Sandrow syndrome: review and redefinition. Am J Med Genet A 2008; 146A: 2557–2565.
Verghese R, Shah H, Rebello G, Joseph B : Pre-axial mirror polydactyly associated with tibial deficiency: a study of the patterns of skeletal anomalies of the foot and leg. J Child Orthop 2007; 1: 49–54.
Kondoh S, Sugawara H, Harada N et al: A novel gene is disrupted at a 14q13 breakpoint of t(2;14) in a patient with mirror-image polydactyly of hands and feet. J Hum Genet 2002; 47: 136–139.
Gurnett CA, Alaee F, Kruse LM et al: Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet 2008; 83: 616–622.
Alvarado DM, McCall K, Aferol H et al: Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet 2011; 20: 3943–3952.
Klopocki E, Ott CE, Benatar N, Ullmann R, Mundlos S, Lehmann K : A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J Med Genet 2008; 45: 370–375.
Semina EV, Reiter R, Leysens NJ et al: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 1996; 14: 392–399.
Szeto DP, Rodriguez-Esteban C, Ryan AK et al: Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev 1999; 13: 484–494.
Marcil A, Dumontier E, Chamberland M, Camper SA, Drouin J : Pitx1 and Pitx2 are required for development of hindlimb buds. Development 2003; 130: 45–55.
Minguillon C, Del Buono J, Logan MP : Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Dev Cell 2005; 8: 75–84.
DeLaurier A, Schweitzer R, Logan M : Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev Biol 2006; 299: 22–34.
Logan M, Tabin CJ : Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 1999; 283: 1736–1739.
Chan YF, Marks ME, Jones FC et al: Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 2010; 327: 302–305.
Lanctot C, Moreau A, Chamberland M, Tremblay ML, Drouin J : Hindlimb patterning and mandible development require the Ptx1 gene. Development 1999; 126: 1805–1810.
Kurth I, Klopocki E, Stricker S et al: Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia. Nat Genet 2009; 41: 862–863.
Klopocki E, Mundlos S : Copy-number variations, noncoding sequences, and human phenotypes. Annu Rev Genomics Hum Genet 2011; 12: 53–72.
Hill RE : How to make a zone of polarizing activity: insights into limb development via the abnormality preaxial polydactyly. Dev Growth Differ 2007; 49: 439–448.
Woods CG, Stricker S, Seemann P et al: Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am J Hum Genet 2006; 79: 402–408.
Acknowledgements
We thank the families for their cooperation and participation in this study. This study was supported by a grant to IK by the Fritz-Thyssen-Stiftung and to EK and SM by the Deutsche Forschungsgemeinschaft.
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Klopocki, E., Kähler, C., Foulds, N. et al. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Eur J Hum Genet 20, 705–708 (2012). https://doi.org/10.1038/ejhg.2011.264
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DOI: https://doi.org/10.1038/ejhg.2011.264
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