Dataset Information

Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation.

ABSTRACT: Clubfoot is one of the most common severe musculoskeletal birth defects, with a worldwide incidence of 1 in 1000 live births. In the present study, we describe a five-generation family with asymmetric right-sided predominant idiopathic clubfoot segregating as an autosomal-dominant condition with incomplete penetrance. Other lower-limb malformations, including patellar hypoplasia, oblique talus, tibial hemimelia, developmental hip dysplasia, and preaxial polydactyly, were also present in some family members. Genome-wide linkage analysis with Affymetrix GeneChip Mapping 10K mapping data from 13 members of this family revealed a multipoint LOD(max) of 3.31 on chromosome 5q31. A single missense mutation (c.388G-->A) was identified in PITX1, a bicoid-related homeodomain transcription factor critical for hindlimb development, and segregated with disease in this family. The PITX1 E130K mutation is located in the highly conserved homeodomain and reduces the ability of PITX1 to transactivate a luciferase reporter. The PITX1 E130K mutation also suppresses wild-type PITX1 activity in a dose-dependent manner, suggesting dominant-negative effects on transcription. The propensity for right-sided involvement in tibial hemimelia and clubfoot suggests that PITX1, or pathways involving PITX1, may be involved in their etiology. Implication of a gene involved in early limb development in clubfoot pathogenesis also suggests additional pathways for future investigations of idiopathic clubfoot etiology in humans.

SUBMITTER: Gurnett CA

PROVIDER: S-EPMC2668044 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation.

Gurnett Christina A CA Alaee Farhang F Kruse Lisa M LM Desruisseau David M DM Hecht Jacqueline T JT Wise Carol A CA Bowcock Anne M AM Dobbs Matthew B MB

American journal of human genetics 20081023 5

Clubfoot is one of the most common severe musculoskeletal birth defects, with a worldwide incidence of 1 in 1000 live births. In the present study, we describe a five-generation family with asymmetric right-sided predominant idiopathic clubfoot segregating as an autosomal-dominant condition with incomplete penetrance. Other lower-limb malformations, including patellar hypoplasia, oblique talus, tibial hemimelia, developmental hip dysplasia, and preaxial polydactyly, were also present in some fam ...[more]

PMID: 18950742

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Project description:Abnormal lower limb biomechanics is speculated to be a risk factor for Achilles tendinopathy. This study systematically reviewed the existing literature to identify, critique and summarise lower limb biomechanical factors associated with Achilles tendinopathy.We searched electronic bibliographic databases (Medline, EMBASE, Current contents, CINAHL and SPORTDiscus) in November 2010. All prospective cohort and case-control studies that evaluated biomechanical factors (temporospatial parameters, lower limb kinematics, dynamic plantar pressures, kinetics [ground reaction forces and joint moments] and muscle activity) associated with mid-portion Achilles tendinopathy were included. Quality of included studies was evaluated using the Quality Index. The magnitude of differences (effect sizes) between cases and controls was calculated using Cohen's d (with 95% CIs).Nine studies were identified; two were prospective and the remaining seven case-control study designs. The quality of 9 identified studies was varied, with Quality Index scores ranging from 4 to 15 out of 17. All studies analysed running biomechanics. Cases displayed increased eversion range of motion of the rearfoot (d = 0.92 and 0.67 in two studies), reduced maximum lower leg abduction (d = -1.16), reduced ankle joint dorsiflexion velocity (d = -0.62) and reduced knee flexion during gait (d = -0.90). Cases also demonstrated a number of differences in dynamic plantar pressures (primarily the distribution of the centre of force), ground reaction forces (large effects for timing variables) and also showed reduced peak tibial external rotation moment (d = -1.29). Cases also displayed differences in the timing and amplitude of a number of lower limb muscles but many differences were equivocal.There are differences in lower limb biomechanics between those with and without Achilles tendinopathy that may have implications for the prevention and management of the condition. However, the findings need to be interpreted with caution due to the limited quality of a number of the included studies. Future well-designed prospective studies are required to confirm these findings.

Project description:BackgroundIndividuals with chronic ankle instability (CAI) exhibit many biomechanical changes to lower limbs during walking. However, only a few studies have investigated the differences in lower limb biomechanics of individuals with CAI compared to healthy controls using a comprehensive approach including kinematic, kinetic and electromyography (EMG) measures. Consequently, the theoretical framework explaining the biomechanical adaptations in individuals with CAI is mostly based on the results of studies including heterogenous methods and participants' specificities (e.g., level of disability). More studies using a comprehensive approach are needed to better understand the biomechanical adaptations associated with CAI. The objective of this case-control study was to identify the kinematic, kinetic and EMG differences between individuals with CAI and healthy controls during walking.MethodsTwenty-eight individuals with CAI and 26 healthy controls were recruited to walk at a self-selected speed during which lower limb kinematics, kinetics and EMG were analysed. Ankle and knee angles and moments as well as gluteus medius, vastus lateralis, gastrocnemius lateralis, peroneus longus and tibialis anterior muscles activity were compared between the CAI and control groups using one-dimensional statistical parametric mapping.ResultsThe CAI group exhibited greater ankle inversion angles from 14 to 48% of the stance phase (%SP) (p = 0.008), ankle eversion moments from 40 to 78%SP (p < 0.001), knee abduction moments from 3 to 6%SP and peroneus longus muscle activity from 0 to 15%SP (p = 0.003) and 60 to 76%SP (p = 0.003) compared to the control group. No significant between-group differences in ankle sagittal and transverse angles and moments, knee angles, knee sagittal and transverse moments as well as gluteus medius, vastus lateralis, gastrocnemius lateralis and tibialis anterior muscles activity were found.ConclusionsDuring the first half of the stance phase, individuals with CAI could be at more risk of sustaining recurrent LAS mostly due to greater ankle inversion angles. However, the greater ankle eversion moments and peroneus longus muscle activity during the second half of the stance phase were an efficient mechanism to correct this maladaptive gait pattern and allowed to attenuate the faulty ankle movements during the pre-swing phase.

Dataset Information

Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation.

Publications

Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation.

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