Mutations in Genes Encoding Fast-Twitch Contractile Proteins Cause Distal Arthrogryposis Syndromes

Abstract

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.

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].…”

Transcription ofDrosophilaTroponin I Gene Is Regulated by Two Conserved, Functionally Identical, Synergistic Elements

“…Several TnI protein isoforms are generated, either from transcription of independent genes (e.g., vertebrates) or from differential splicing of a single gene primary transcript (e.g., Drosophila). Amino acid substitutions in constitutive or alternatively spliced exons in TnI can lead to pathological conditions such as familial hypertrophic cardiomyopathy (Carrier et al, 1993;Coonar and McKenna, 1997) and distal arthrogryposis (Sung et al, 2003), due to abnormal interactions with other sarcomere components. Also, TnI is a relevant indicator of heart failure (Lewinter and Vanburen, 2002) and a potent angiogenesis inhibitor through its interaction with polycystin-2 (Li et al, 2003).…”

Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

“…TPM2 is expressed in both slow (type 1), and, to a lesser extent, fast (type 2) muscle fibres, whereas TPM3 encodes the slow-specific isoform aTm slow . 25 Mutations in slow muscle fibre-specific TPM3 cause NM 6,13,17,18,26 and have recently been shown to perhaps be a relatively common cause of congenital fibre type disproportion (CFTD), 27 while mutations of TPM2, expressed in all muscle fibres, have been reported in patients either with NM, 7 distal arthrogryposis, 28 or cap disease. 29 TPM1 mutations are known to cause dilated and hypertrophic cardiomyopathies (MIM 115196).…”