Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B.

摘要: To the Editor: We recently reported that distal arthrogryposis type 1 (DA1 [MIM 108120]) and 2B (DA2B 601680]), both of which are characterized by congenital contractures hands/wrists feet/ankles (Bamshad et al. 1996), caused mutations in TNNI2 TPM2, respectively (Sung 2003). encodes an isoform troponin I; this isoforms T (TnT) C constitute complex fast-twitch myofibers. This is primary sensor intracellular Ca+2 ion concentration skeletal muscle, and, consequently, it important regulator muscle contraction. The myofibers exerts its effect on contraction binding to actin β-tropomyosin, product encoded TPM2 (Clark 2002). These findings led us hypothesize genes encoding other contractile-apparatus proteins specific might also cause multiple contractures. We now report discovery a mutation, TNNT3 (the gene TnT myofibers), causes DA2B. We sequenced 47 families with either DA2A (classical Freeman-Sheldon syndrome 193700]) or DA2B. found G→A missense at nucleotide position 188 exon 9 cDNA (GenBank accession number {"type":"entrez-nucleotide","attrs":{"text":"NM_006757","term_id":"184172387","term_text":"NM_006757"}}NM_006757), arginine-to-histidine substitution amino acid residue 63 (R63H) mother DA2B her two affected children (fig. 1). For several reasons, mutation probably disease causing. First, identified proband was present all family members There is, however, probability 1/4 pattern occurred chance. inference R63H would be strengthened demonstrating did not occur unaffected parents I-2 (i.e., de novo mutation). However, only living parent unavailable for study. Second, change 488 chromosomes from ethnically matched control group we screened. Third, results conserved known 2), implying difference likely have structural and/or functional consequences. Fourth, homologous cardiac-specific form cardiomyopathy (Varnava 1999). Figure  1 Electropherogram heterozygosity confirm presence incorporated MluI restriction site into amplicon ... Figure  2 Amino sequences human, mouse, bird, aligned human slow-twitch cardiac TnT. Because been ∼10% cases DA2B, suspected genetically heterogeneous condition date, linkage studies any candidate regions than chromosome 11p15.5 (Krakowiak 1997). observation can confirms heterogeneous. Because located within hundred kilobases one another 11p15.5, conclusion consistent our prior Nevertheless, absence most suggests regulatory these harbor yet DA2B. Although distinguished direct testing TNNI2, there appear few, if any, ways distinguish, basis clinical characteristics, responsible. may, sufficient phenotypic differences between DA1 distinguish them. In addition facial features (e.g., small mouth prominent nasolabial folds) common but lacking individuals DA1, characteristics vertical talus scoliosis) more frequent DA1. Additionally, hand foot patients resilient medical intervention occupational therapy casting). It should cautioned, too few lend much credibility broad generalizations about genotype-phenotype relationships. The mechanism unknown. Missense TNNT2—a paralogue, TnT—cause ∼15% familial hypertrophic (Watkins 1995). One arginine-to-leucine 94 (R94L), myofiber 1999). R94L perturbs tropomyosin-dependent functions TnT, including tropomyosin (Palm 2001), due, part, impaired flexibility N-terminal tail (Hinkle Tobacman may similar myofibers. The theme emerging previous perturbation function contractile apparatus during fetal development otherwise normal neuromuscular examination. On result, seems plausible polymorphisms troponin-tropomyosin influence individual’s susceptibility isolated idiopathic clubfoot) modify phenotype myopathic disorders Duchenne muscular dystrophy). At minimum, underscores existence new class genetic diseases lack many typical heritable myopathy.