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

  • Christina A. Gurnett
  • Farhang Alaee
  • David Desruisseau
  • Stephanie Boehm
  • Matthew B. Dobbs
Symposium: Clubfoot: Etiology and Treatment

Abstract

Arthrogryposis presents with lower limb contractures that resemble clubfoot and/or vertical talus. Recently, mutations in skeletal muscle contractile genes MYH3 (myosin heavy chain 3), TNNT3 (troponin T3), and TPM2 (tropomyosin 2) were identified in patients with distal arthrogryposis DA2A (Freeman-Sheldon syndrome) or DA2B (Sheldon-Hall syndrome). We asked whether the contractile genes responsible for distal arthrogryposis are also responsible for cases of familial clubfoot or vertical talus. We determined the frequency of MYH3, TNNT3, and TPM2 mutations in patients with idiopathic clubfoot, vertical talus, and distal arthrogryposis type 1 (DA1). We resequenced the coding exons of the MYH3, TNNT3, and TPM2 genes in 31 patients (five with familial vertical talus, 20 with familial clubfoot, and six with DA1). Variants were evaluated for segregation with disease in additional family members, and the frequency of identified variants was determined in a control population. In one individual with DA1, we identified a de novo TNNT3 mutation (R63H) previously identified in an individual with DA2B. No other causative mutations were identified, though we found several previously undescribed single-nucleotide polymorphisms of unknown importance. Although mutations in MYH3, TNNT3, and TPM2 are frequently associated with distal arthrogryposis syndromes, they were not present in patients with familial vertical talus or clubfoot. The TNNT3 R63H recurrent mutation identified in two unrelated individuals may be associated with either DA1 or DA2B.

Level of Evidence: Level II, prospective study. See the Guidelines for Authors for a complete description of levels of evidence.

Keywords

Myosin Heavy Chain Clubfoot Ponseti Method MYH3 Gene Idiopathic Clubfoot 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Bamshad M, Bohnsack JF, Jorde LB, Carey JC. Distal arthrogryposis type 1: clinical analysis of a large kindred. Am J Med Genet. 1996;65:282–285.PubMedCrossRefGoogle Scholar
  2. 2.
    Bamshad M, Jorde LB, Carey JC. A revised and extended classification of the distal arthrogryposes. Am J Med Genet. 1996;65:277–281.PubMedCrossRefGoogle Scholar
  3. 3.
    Beals RK. The distal arthrogryposes: a new classification of peripheral contractures. Clin Orthop Relat Res. 2005;435:203–210.PubMedCrossRefGoogle Scholar
  4. 4.
    Boehm S, Limpaphayom N, Alaee F, Sinclair MF, Dobbs MB. Early results of the Ponseti method for the treatment of clubfoot in distal arthrogryposis. J Bone Joint Surg Am. 2008;90:1501–1507.PubMedCrossRefGoogle Scholar
  5. 5.
    Buvoli M, Hamady M, Leinwand LA, Knight R. Bioinformatics assessment of beta-myosin mutations reveals myosin’s high sensitivity to mutations. Trends Cardiovasc Med. 2008;18:141–149.PubMedCrossRefGoogle Scholar
  6. 6.
    Cooper DM, Dietz FR. Treatment of idiopathic clubfoot. A thirty-year follow-up note. J Bone Joint Surg Am. 1995;77:1477–1489.PubMedGoogle Scholar
  7. 7.
    Dimeglio A, Bensahel H, Souchet P, Mazeau P, Bonnet F. Classification of clubfoot. J Pediatr Orthop B. 1995;4:129–136.PubMedGoogle Scholar
  8. 8.
    Dobbs MB, Gurnett CA, Robarge J, Gordon JE, Morcuende JA, Bowcock AM. Variable hand and foot abnormalities in family with congenital vertical talus and CDMP-1 gene mutation. J Orthop Res. 2005;23:1490–1494.PubMedGoogle Scholar
  9. 9.
    Dobbs MB, Purcell DB, Nunley R, Morcuende JA. Early results of a new method of treatment for idiopathic congenital vertical talus. J Bone Joint Surg Am. 2006;88:1192–1200.PubMedCrossRefGoogle Scholar
  10. 10.
    Dobbs MB, Purcell DB, Nunley R, Morcuende JA. Early results of a new method of treatment for idiopathic congenital vertical talus. Surgical technique. J Bone Joint Surg Am. 2007;89 Suppl 2 Pt.1:111–121.Google Scholar
  11. 11.
    Eller M, Stedman HH, Sylvester JE, Fertels SH, Wu QL, Raychowdhury MK, Rubinstein NA, Kelly AM, Sarkar S. Human embryonic myosin heavy chain cDNA. Interspecies sequence conservation of the myosin rod, chromosomal locus and isoform specific transcription of the gene. FEBS Lett. 1989;256:21–28.PubMedCrossRefGoogle Scholar
  12. 12.
    Gurnett CA, Boehm S, Connolly A, Reimschisel T, Dobbs MB. Impact of congenital talipes equinovarus etiology on treatment outcomes. Dev Med Child Neurol. 2008;50:498–502.PubMedCrossRefGoogle Scholar
  13. 13.
    Gurnett CA, Keppel C, Bick J, Bowcock AM, Dobbs MB. Absence of HOXD10 mutations in idiopathic clubfoot and sporadic vertical talus. Clin Orthop Relat Res. 2007;462:27–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Hall JG. Arthrogryposis multiplex congenita: etiology, genetics, classification, diagnostic approach, and general aspects. J Pediatr Orthop B. 1997;6:159–166.PubMedGoogle Scholar
  15. 15.
    Hall JG, Reed SD, Greene G. The distal arthrogryposes: delineation of new entities–review and nosologic discussion. Am J Med Genet. 1982;11:185–239.PubMedCrossRefGoogle Scholar
  16. 16.
    Laaveg SJ, Ponseti IV. Long-term results of treatment of congenital club foot. J Bone Joint Surg Am. 1980;62:23–31.PubMedGoogle Scholar
  17. 17.
    Lochmiller C, Johnston D, Scott A, Risman M, Hecht JT. Genetic epidemiology study of idiopathic talipes equinovarus. Am J Med Genet. 1998;79:90–96.PubMedCrossRefGoogle Scholar
  18. 18.
    Margulies EH, Kardia SL, Innis JW. A comparative molecular analysis of developing mouse forelimbs and hindlimbs using serial analysis of gene expression (SAGE). Genome Res. 2001;11:1686–1698.PubMedCrossRefGoogle Scholar
  19. 19.
    Robinson P, Lipscomb S, Preston LC, Altin E, Watkins H, Ashley CC, Redwood CS. Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function. FASEB J. 2007;21:896–905.PubMedCrossRefGoogle Scholar
  20. 20.
    Shou S, Scott V, Reed C, Hitzemann R, Stadler HS. Transcriptome analysis of the murine forelimb and hindlimb autopod. Dev Dyn. 2005;234:74–89.PubMedCrossRefGoogle Scholar
  21. 21.
    Stevenson DA, Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006;117:754–762.PubMedCrossRefGoogle Scholar
  22. 22.
    Sung SS, Brassington AM, Grannatt K, Rutherford A, Whitby FG, Krakowiak PA, Jorde LB, Carey JC, Bamshad M. Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet. 2003;72:681–690.PubMedCrossRefGoogle Scholar
  23. 23.
    Sung SS, Brassington AM, Krakowiak PA, Carey JC, Jorde LB, Bamshad M. Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Am J Hum Genet. 2003;73:212–214.PubMedCrossRefGoogle Scholar
  24. 24.
    Sunyaev S, Ramensky V, Koch I, Lathe W 3rd, Kondrashov AS, Bork P. Prediction of deleterious human alleles. Hum Mol Genet. 2001;10:591–597.PubMedCrossRefGoogle Scholar
  25. 25.
    Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006;38:561–565.PubMedCrossRefGoogle Scholar
  26. 26.
    Veugelers M, Bressan M, McDermott DA, Weremowicz S, Morton CC, Mabry CC, Lefaivre JF, Zunamon A, Destree A, Chaudron JM, Basson CT. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med. 2004;351:460–469.PubMedCrossRefGoogle Scholar
  27. 27.
    Wynne-Davies R. Family studies and the cause of congenital clubfoot. talipes equinovarus, talipes calcaneo-valgus and metatarsus varus. J Bone Joint Surg Br. 1964;46:445–463.PubMedGoogle Scholar
  28. 28.
    Wynne-Davies R. Genetic and environmental factors in the etiology of talipes equinovarus. Clin Orthop Relat Res. 1972;84:9–13.PubMedCrossRefGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons 2009

Authors and Affiliations

  • Christina A. Gurnett
    • 1
    • 2
    • 3
  • Farhang Alaee
    • 4
  • David Desruisseau
    • 4
  • Stephanie Boehm
    • 4
  • Matthew B. Dobbs
    • 5
    • 6
  1. 1.Department of Neurology Washington University School of MedicineSt LouisUSA
  2. 2.Department of Pediatrics Washington University School of Medicine St Louis USA
  3. 3.Department of Orthopaedic SurgeryWashington University School of MedicineSt LouisUSA
  4. 4.Department of Orthopaedic SurgeryWashington University School of MedicineSt LouisUSA
  5. 5.Department of Orthopaedic SurgeryWashington University School of MedicineSt LouisUSA
  6. 6.St Louis Shriners Hospital for ChildrenSt LouisUSA

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