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

SS Sung, AME Brassington, PA Krakowiak… - The American Journal of …, 2003 - cell.com
SS Sung, AME Brassington, PA Krakowiak, JC Carey, LB Jorde, M Bamshad
The American Journal of Human Genetics, 2003cell.com
We recently reported that distal arthrogryposis type 1 (DA1 [MIM 108120]) and distal
arthrogryposis type 2B (DA2B [MIM 601680]), both of which are characterized by congenital
contractures of the hands/wrists and feet/ankles (Bamshad et al. 1996), are caused by
mutations in TNNI2 and TPM2, respectively (Sung et al. 2003). TNNI2 encodes an isoform of
troponin I; this isoform and the isoforms of troponin T (TnT) and troponin C constitute the
troponin complex of fast-twitch myofibers. This complex is the primary sensor of intracellular …
We recently reported that distal arthrogryposis type 1 (DA1 [MIM 108120]) and distal arthrogryposis type 2B (DA2B [MIM 601680]), both of which are characterized by congenital contractures of the hands/wrists and feet/ankles (Bamshad et al. 1996), are caused by mutations in TNNI2 and TPM2, respectively (Sung et al. 2003). TNNI2 encodes an isoform of troponin I; this isoform and the isoforms of troponin T (TnT) and troponin C constitute the troponin complex of fast-twitch myofibers. This complex is the primary sensor of intracellular Ca+ 2 ion concentration in skeletal muscle, and, consequently, it is an important regulator of muscle contraction. The troponin complex of fast-twitch myofibers exerts its effect on muscle contraction by binding to actin and b-tropomyosin, the product encoded by TPM2 (Clark et al. 2002). These findings led us to hypothesize that mutations in genes encoding other contractile-apparatus proteins specific to fast-twitch myofibers might also cause multiple congenital contractures. We now report the discovery of a mutation, in TNNT3 (the gene encoding TnT specific to fast-twitch myofibers), that causes DA2B. We sequenced TNNT3 in 47 families with either DA2A (classical Freeman-Sheldon syndrome [MIM 193700]) or DA2B. We found a GrA missense mutation, at nucleotide position 188 in exon 9 of the TNNT3 cDNA (Gen-Bank accession number NM_006757), that causes an arginine-to-histidine substitution at amino acid residue 63 (R63H) of TnT in a mother with DA2B and her two affected children (fig. 1). For several reasons, this mutation is probably disease causing. First, the mutation identified in the proband was also present in all affected family members (fig. 1). There is, however, a probability of 1/4 that this pattern occurred by chance. The inference that R63H causes DA2B would be strengthened by demonstrating that this mutation did not occur in the unaffected parents of I-2 (ie, that it is a de novo mutation). However, the only living parent of I-2 is unavailable for study. Second, this change was not found in 488 chromosomes from an ethnically matched control group that we screened. Third, R63H results in the substitution of an amino acid residue that is conserved in all known isoforms of TnT (fig. 2), implying that this difference is likely to have structural and/or functional consequences. Fourth, substitution of the homologous amino acid residue in the cardiac-specific form of TnT causes cardiomyopathy (Varnava et al. 1999). Because mutations in TNNI2 have been found in only∼ 10% of cases of DA2B, we suspected that DA2B is a genetically heterogeneous condition (Sung et al. 2003). To date, however, linkage studies have not identified any candidate regions other than chromosome 11p15. 5 (Krakowiak et al. 1997). The observation that DA2B can be caused by mutations in either TNNI2 or TNNT3 confirms that DA2B is genetically heterogeneous. Because TNNI2 and TNNT3 are located within several hundred kilobases of one another on chromosome 11p15. 5, this conclusion is also consistent with the results of our prior linkage studies (Sung et al. 2003). Nevertheless, the absence of mutations in TNNI2 or TNNT3 in most cases of DA2B suggests either that regulatory regions of these genes harbor mutations or that mutations in genes yet to be identified also cause DA2B.
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