Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome

Abstract

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.

Update on Clubfoot: Etiology and Treatment

“…PITX1 is the first gene implicated in clubfoot that explains the specific involvement of the foot, since PITX1 is expressed nearly exclusively in the hindlimb and is responsible for rapid evolutionary changes in pelvic morphology in lower vertebrates [58]. Specific involvement of the foot also appears to exclude many of the skeletal muscle contractile genes that are responsible for distal arthrogryposis [62,63,65,70] in the causation of idiopathic clubfoot, as mutations in these genes cause both upper and lower extremity involvement and were not identified in idiopathic clubfoot patients [29].…”

Skeletal Muscle Contractile Gene (TNNT3, MYH3, TPM2) Mutations Not Found in Vertical Talus or Clubfoot

“…That the recurrent TNNT3 R63H mutation may cause either DA1 or DA2B suggests there may be other factors modifying the phenotype. Phenotypic variability in distal arthrogryposis occurring with identical MYH3 mutations has been described previously [25]. However, it is admittedly difficult to diagnose mild forms of facial weakness, particularly in infancy, and thus it may be difficult to clearly distinguish patients with DA1 (affecting only the hands and feet) from other types of distal arthrogryposis.…”

“…The prevalence of DA1 is likely higher than the other forms of arthrogryposis [15], occurring in 1:10,000 to 1:50,000 births [1]. While mutations in MYH3 account for 93% of patients with Freeman-Sheldon syndrome (DA2A) and 32% of patients with Sheldon-Hall syndrome (DA2B) [25], the frequency of MYH3 mutations in patients with DA1 appears to be low; we found no mutations in this gene in any of our six patients. Furthermore, after screening for mutations in MYH3, TNNT3, and TPM2, a mutation was found in only one of six patients.…”

“…As a class, distal arthrogryposis may result from mutations in five skeletal muscle contractile or regulatory genes: myosin heavy chain (MYH3, MYH8), troponin I (TNNI2), troponin T (TNNT3), and tropomyosin (TPM2) [22,25,26]. Mutations in these genes have been described most frequently in patients with the more severe forms of distal arthrogryposis, including Freeman-Sheldon Syndrome (DA2A) and Sheldon-Hall Syndrome (DA2B) [21], in which facial contractures are also present.…”

Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome

“…The gene is known to be involved in DA) syndromes that constitute a group of disorders characterized by multiple congenital contractures of the upper and lower limbs. [7][8][9][10] Variants in MYH3 cause DA1 (OMIM #108120), 11,12 DA2A (Freeman-Sheldon syndrome; OMIM #193700) [13][14][15] and DA2B (Sheldon-Hall syndrome; OMIM #601680). 16,17 Interestingly, recent findings from Chong et al 18 indicate that MYH3 is also involved in autosomal dominant MPS that, in addition to congenital contractures of the limbs, is characterized by multiple pterygia and skeletal anomalies including fusion of vertebra and scoliosis.…”