PITX1 – Clubfoot

PITX1 is a paired-like homeodomain transcription factor critical for hindlimb development. Heterozygous variants in PITX1 have been implicated in isolated congenital talipes equinovarus (clubfoot), a common musculoskeletal disorder characterized by a rigid inward and downward turning of the foot. Early linkage analysis in a five-generation family demonstrated autosomal-dominant inheritance with incomplete penetrance and a multipoint LOD(max) of 3.31 on chromosome 5q31, leading to the identification of a missense mutation c.388G>A (p.Glu130Lys) segregating with right-sided predominant clubfoot (8 affected relatives) PMID:18950742.

Subsequent genome-wide copy number analysis in 413 isolated clubfoot patients identified 74 rare gene-containing CNVs, of which 12 rare CNVs containing PITX1 segregated with disease in multiplex pedigrees, supporting a role for dosage alterations of early limb developmental regulators in clubfoot pathogenesis PMID:22892537. In contrast, targeted sequencing and SNP array analysis of 162 Italian idiopathic clubfoot patients found no pathogenic PITX1 single-nucleotide or CNV variants, indicating that PITX1 alterations account for only a minority of cases in some populations PMID:36360195.

Variants reported in clubfoot include the pathogenic missense mutation c.388G>A (p.Glu130Lys) and rare heterozygous deletions or duplications encompassing PITX1. No recurrent founder alleles have been described.

Functional assays demonstrate that the PITX1 p.Glu130Lys variant lies within the highly conserved homeodomain, significantly reduces transactivation of luciferase reporters, and exerts a dominant-negative effect on wild-type PITX1 activity in a dose-dependent manner, impairing hindlimb gene expression programs PMID:18950742. In tendon cells, PITX1 binds the promoter of SIRT1 to regulate acetylation states that modulate retinoic acid signaling; downregulation of PITX1 leads to increased CRABP2 acetylation and enhanced RARβ2 expression, linking PITX1 loss to clubfoot-like phenotypes via disturbed RA pathways PMID:31527569.

The collective data support a mechanism of dominant-negative interference and dosage sensitivity of PITX1 in clubfoot, with functional concordance between human mutations and limb-specific gene regulatory pathways. However, the rarity of PITX1 variants and absence of association in some cohorts highlight locus heterogeneity and incomplete penetrance.

Key Take-home: Heterozygous PITX1 mutations and CNVs cause autosomal-dominant clubfoot through dominant-negative effects on hindlimb developmental pathways, informing genetic testing and counseling in familial cases.

References

• American Journal of Human Genetics • 2008 • Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. PMID:18950742
• European Journal of Human Genetics • 2013 • Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development. PMID:22892537
• Genes • 2022 • What Is the Exact Contribution of PITX1 and TBX4 Genes in Clubfoot Development? An Italian Study. PMID:36360195
• Medical Science Monitor • 2019 • Retinoic Acid Promotes Retinoic Acid Signaling by Suppression of Pitx1 In Tendon Cells: A Possible Mechanism of a Clubfoot-Like Phenotype Induced by Retinoic Acid. PMID:31527569

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