ArticleHuman molecular genetics2011
Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 2 of them syntheses that pooled it.
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Who cites it
46 citing papers in PubMed, 2 syntheses or guidelines pooled it, 86 citations in OpenAlex.
- The molecular genetics of human appendicular skeleton.Molecular genetics and genomics : MGG · 2022Pooled it
- The etiology of idiopathic congenital talipes equinovarus: a systematic review.Journal of orthopaedic surgery and research · 2018Pooled it
- A New Case ofClinics and practice · 2026Article
- Genetics, epidemiology and management of clubfoot and related disorders.Genes & diseases · 2025Review
- Thalidomide-induced limb malformations: an update and reevaluation.Archives of toxicology · 2025Review
- Same trait, different genes: pelvic spine loss in three brook stickleback populations in Alberta, Canada.Evolution letters · 2025Article
- Scoliosis as a Paradigm of Pathological Spinal Curvature: Molecular Mechanisms and Imaging Innovations : Molecular and Imaging Insights in Scoliosis.Galen medical journal · 2025Review
- Prenatal Counseling for Congenital Clubfoot.Journal of the Pediatric Orthopaedic Society of North America · 2024Review
- Harnessing the Biomimetic Effect of Macromolecular Crowding in the Cell-Derived Model of Clubfoot Fibrosis.Biomacromolecules · 2024Article
- Comparison of kinematics and pedobarography findings between the unaffected foot of patients with unilateral clubfoot and controls.International orthopaedics · 2024Article
- Boundary stacking interactions enable cross-TAD enhancer-promoter communication during limb development.Nature genetics · 2024Article
- Incidence and prevalence of congenital clubfoot in Apulia: a regional model for future prospective national studies.Italian journal of pediatrics · 2023Review
- PITX1 plays essential functions in cancer.Frontiers in oncology · 2023Review
- Advances in epigenetic research of adolescent idiopathic scoliosis and congenital scoliosis.Frontiers in genetics · 2023Review
- What Is the Exact Contribution ofGenes · 2022Article
- Regulation ofFrontiers in pediatrics · 2022Article
- Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer.Nature communications · 2021Article
- (Non)Parallel developmental mechanisms in vertebrate appendage reduction and loss.Ecology and evolution · 2021Review
- Tbx4 function during hindlimb development reveals a mechanism that explains the origins of proximal limb defects.Development (Cambridge, England) · 2021Article
- A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.Genes · 2021Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Clubfoot affects 1 in 1000 live births, although little is known about its genetic or developmental basis. We recently identified a missense mutation in the PITX1 bicoid homeodomain transcription factor in a family with a spectrum of lower extremity abnormalities, including clubfoot. Because the E130K mutation reduced PITX1 activity, we hypothesized that PITX1 haploinsufficiency could also cause clubfoot. Using copy number analysis, we identified a 241 kb chromosome 5q31 microdeletion involving PITX1 in a patient with isolated familial clubfoot. The PITX1 deletion segregated with autosomal dominant clubfoot over three generations. To study the role of PITX1 haploinsufficiency in clubfoot pathogenesis, we began to breed Pitx1 knockout mice. Although Pitx1(+/-) mice were previously reported to be normal, clubfoot was observed in 20 of 225 Pitx1(+/-) mice, resulting in an 8.9% penetrance. Clubfoot was unilateral in 16 of the 20 affected Pitx1(+/-) mice, with the right and left limbs equally affected, in contrast to right-sided predominant hindlimb abnormalities previously noted with complete loss of Pitx1. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1(-/-) E12.5 hindlimb buds compared with the wild-type, suggesting that muscle hypoplasia was due to abnormal early muscle development and not disuse atrophy. Our morphological data suggest that PITX1 haploinsufficiency may cause a developmental field defect preferentially affecting the lateral lower leg, a theory that accounts for similar findings in human clubfoot.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.