The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders.

Alternative transcription factor sigma B of Bacillus subtilis controls a stationary-phase regulon induced under growth conditions that do not favor sporulation. Little is known about the metabolic signals and protein factors regulating the activity of sigma B. The operon containing the sigma B structural gene has the gene order orfV-orfW-sigB-rsbX, and operon expression is autoregulated positively by sigma B and negatively by the rsbX product (rsbX = regulator of sigma B). To establish the roles of the orfV and orfW products, orfV and orfW null and missense mutations were constructed and tested for their effects on expression of the sigma B-dependent genes ctc and csbA. These mutations were tested in two contexts: in the first, the sigB operon was under control of its wild-type, sigma B-dependent promoter, and in the second, the sigB operon promoter was replaced by the inducible Pspac promoter. The principal findings are that (i) the orfV (now called rsbV) product is a positive regulator of sigma B-dependent gene expression; (ii) the orfW (now called rsbW) product is a negative regultor of such expression; (iii) sigma B is inactive during logarithmic growth unless the rsbW product is absent; (iv) the rsbX, rsbV, and rsbW products have a hierarchical order of action; and (v) both the rsbV and rsbW products appear to regulate sigma B activity posttranslationally. There are likely to be at least two routes by which information can enter the system to regulate sigma B: via the rsbX product, and via the rsbV and rsbW products.

Mutations in TBX5, a T-box-containing transcription factor, cause cardiac and limb malformations in individuals with Holt-Oram syndrome (HOS). Mutations that result in haploinsufficiency of TBX5 are purported to cause cardiac and limb defects of similar severity, whereas missense mutations, depending on their location in the T box, are thought to cause either more severe heart or more severe limb abnormalities. These inferences are, however, based on the analysis of a relatively small number of independent cases of HOS. To better understand the relationship between mutations in TBX5 and the variable expressivity of HOS, we screened the coding and noncoding regions of TBX5 and SALL4 for mutations in 55 probands with HOS. Seventeen mutations, including six missense mutations in TBX5 and two mutations in SALL4, were found in 19 kindreds with HOS. Fewer than 50% of individuals with nonsense or frameshift mutations in TBX5 had heart and limb defects of similar severity, and only 2 of 20 individuals had heart or limb malformations of the severity predicted by the location of their mutations in the T box. These results suggest that neither the type of mutation in TBX5 nor the location of a mutation in the T box is predictive of the expressivity of malformations in individuals with HOS.

The clinical characteristics and natural history of FSS distinguish it from other forms of arthrogryposis, yet FSS is frequently misdiagnosed. Children with FSS require considerable nutritional, surgical, and rehabilitative intervention. Such intensive therapeutic demands differ substantially from most other congenital contracture syndromes. These findings underscore the necessity of making an accurate diagnosis.