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At least 451 records · Page 25Linked to original sources
PubMed2003

Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.

The distal arthrogryposes (DAs) are a group of disorders characterized by multiple congenital contractures of the limbs. We previously mapped a locus for DA type 2B (DA2B), the most common of the DAs, to chromosome 11. We now report that DA2B is caused by mutations in TNNI2 that are predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI) specific to the troponin-tropomyosin (Tc-Tm) complex of fast-twitch myofibers. Because the DAs are genetically heterogeneous, we sought additional candidate genes by examining modifiers of mutant Drosophila isoforms of TnI. One of these modifiers, Tm2, encodes tropomyosin, another component of the Tc-Tm complex. A human homologue of Tm2, TPM2, encodes beta-tropomyosin and maps to the critical interval of DA type 1 (DA1). We discovered that DA1 is caused by substitution of a highly conserved amino acid residue in beta-tropomyosin. These findings suggest that DAs, in general, may be caused by mutations in genes encoding proteins of the contractile apparatus specific to fast-twitch myofibers. This provides a new opportunity to directly study the etiology and pathogenesis of multiple-congenital-contracture syndromes.

Amino Acid Sequence↗
PubMed2006

Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function.

Distal arthrogryposes (DAs) are a group of disorders characterized by congenital contractures of distal limbs without overt neurological or muscle disease. Unexpectedly, mutations in genes encoding the fast skeletal muscle regulatory proteins troponin T (TnT), troponin I (TnI), and beta-tropomyosin (beta-TM) have been shown to cause autosomal dominant DA. We tested how these mutations affect contractile function by comparing wild-type (WT) and mutant proteins in actomyosin ATPase assays and in troponin-replaced rabbit psoas fibers. We have analyzed all four reported mutants: Arg63His TnT, Arg91Gly beta-TM, Arg174Gln TnI, and a TnI truncation mutant (Arg156ter). Thin filaments, reconstituted using actin and WT troponin and beta-TM, activated myosin subfragment-1 ATPase in a calcium-dependent, cooperative manner. Thin filaments containing either a troponin or beta-TM DA mutant produced significantly enhanced ATPase rates at all calcium concentrations without alternating calcium-sensitivity or cooperativity. In troponin-exchanged skinned fibers, each mutant caused a significant increase in Ca2+ sensitivity, and Arg156ter TnI generated significantly higher maximum force. Arg91Gly beta-TM was found to have a lower actin affinity than WT and form a less stable coiled coil. We propose the mutations cause increased contractility of developing fast-twitch skeletal muscles, thus causing muscle contractures and the development of the observed limb deformities.

Actins↗
PubMedDate not supplied

Talectomy for clubfoot in arthrogryposis.

We reviewed the results of 101 talectomies in 56 patients with arthrogrypotic clubfeet. The average age at the time of surgery was 4.3 years and the mean follow-up was 6 years. Talectomy was performed as a primary procedure in 16 feet and as a salvage procedure in 85 feet that underwent other surgical procedures before talectomy. We graded our results as good when the foot was plantigrade, able to wear regular shoes, pain free, and, very important, patient satisfaction. We used a chi2 statistical test and, after comparing results with age <4 to >4 years at time of surgery, tendo Achilles tenotomy, time of casting, radiological complete excision of talus, and transcalcaneal pin placement, only the immobilization time needed to be statistically significant to achieve a good result. We conclude that feet must be individualized for treatment and that, after reduction of the calcaneus in the mortise, a short leg cast must be placed for 8 weeks to maintain position and alignment.

Achilles Tendon↗
PubMed1983

Ambulation in severe arthrogryposis.

Functional ambulation occurred in 22 of 36 severely affected arthrogrypotic patients. Functional ambulation in these patients required hip motion to within 30 degrees of full extension and knee motion to within 20 degrees of full extension. Ambulation also required hip extensor strength of good (grade 4), quadriceps strength of fair (grade 3), or crutchable upper extremities and orthotic substitutes. Foot and spine deformities also interfered with ambulatory ability.

Adolescent↗
PubMed1993

Distal arthrogryposis with autosomal dominant inheritance and reduced penetrance in females: the Gordon syndrome.

A family is reported in which camptodactyly, club foot, pectus excavatum and undescended testes are transmitted as an autosomal dominant with reduced penetrance and variable expressivity, affecting 13 members through five generations. Penetrance is more reduced in females than in males and asymptomatic carriers are always females. Similar findings were previously described in two other families reported by Gordon et al. (1962) and Halal & Fraser (1979).

Abnormalities, Multiple↗