Alternative titles; symbols
HGNC Approved Gene Symbol: MYH8
SNOMEDCT: 8757006;
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:10,390,322-10,421,950 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Carney complex variant | 608837 | 3 | |
| Trismus-pseudocamptodactyly syndrome | 158300 | Autosomal dominant | 3 |
For background information on the myosin heavy chain genes, see MYH1 (160730).
Karsch-Mizrachi et al. (1990) isolated and sequenced cDNA that encodes a human perinatal skeletal myosin heavy chain.
By study of somatic hybrid cell DNAs, Karsch-Mizrachi et al. (1990) assigned the gene to 17p13-p11.2 in the cluster of skeletal MHC-encoding genes. Soussi-Yanicostas et al. (1993) demonstrated that at least 5 skeletal myosin heavy chain genes are organized in a cluster within a 320-kb SalI genomic fragment. Thus, the MYH8 gene is presumably located in 17p13.1, the site of the other genes in this cluster (see 160730).
Weiss et al. (1999) stated that embryonic (MYH3; 160720) and perinatal MYHCs predominate early during skeletal muscle development, persist in certain specialized muscles, such as extraocular and masseter, and are reexpressed in regenerating muscles.
In a large family with Carney complex variant associated with distal arthrogryposis (608837), Veugelers et al. (2004) demonstrated linkage to 17p13.1-p12 (maximum multipoint lod score = 4.39 at marker D17S1852). Sequence analysis identified an arg674-to-gln mutation in the MYH8 gene (R674Q; 160741.0001) in affected individuals. The R674Q mutation was also identified in affected members of 2 other families with trismus-pseudocamptodactyly syndrome (158300). Veugelers et al. (2004) also identified nonsynonymous MYH8 polymorphisms in patients with cardiac myxoma syndromes but without arthrogryposis.
Stratakis et al. (2004) argued that the syndrome described by Veugelers et al. (2004) was not in fact a variant of Carney complex. They stated that among more than 500 patients with the Carney complex in their database, there was none with trismus-pseudocamptodactyly syndrome. They suggested that trismus-pseudocamptodactyly syndrome with freckling may or may not be associated with familial myxomas and may or may not be caused by a single mutation of the MYH8 gene, but their data led them to conclude that this disorder is distinct from the Carney complex.
Toydemir et al. (2006) identified the R674Q mutation in all affected members of 4 families with trismus-pseudocamptodactyly syndrome: 3 U.S. kindreds, including 1 family previously reported by Chen et al. (1992), and 1 Dutch kindred that was previously described by Ter Haar and Van Hoof (1974). Analysis of haplotype sharing revealed that while each of the U.S. pedigrees shared the same MYH8 haplotype, this haplotype was not shared by the Dutch kindred. None of the affected individuals had multiple hyperpigmented macules or cardiac myxomas, and the R674Q mutation was not found in 49 unrelated cases of Carney complex who were negative for mutation in the PRKAR1A gene (188830). Toydemir et al. (2006) concluded that Dutch and U.S. pedigrees with trismus-pseudocamptodactyly syndrome do not share a founder mutation, and that R674Q rarely, if ever, causes Carney complex.
Veugelers et al. (2004) described a Caucasian Belgian family, originally reported by Chaudron et al. (1992), with Carney complex variant associated with distal arthrogryposis (608837). In 18 affected members of the family, they identified a 2094G-A transition in exon 16 of the MYH8 gene, resulting in an arg674-to-gln (R674Q) substitution. The arginine residue at position 674 is highly conserved evolutionarily, localizes to the actin-binding domain of the perinatal myosin head, and is close to the ATP-binding site. Penetrance of the disorder was complete, although expressivity was highly variable. Three affected family members had had cardiac myxomas, and all affected family members who were available for a complete examination had spotty skin pigmentation alone or in combination with cutaneous lesions. Most of the family members had distal arthrogryposis, including pseudocamptodactyly of the hands and feet, trismus, or both, which improved symptomatically with aging. Two family members had required palliative hand surgery, and 1 had had foot surgery. Stratakis et al. (2004) argued that the syndrome described by Veugelers et al. (2004) was not a variant of Carney complex but was in fact distinct from the Carney complex.
In affected members of branches of 2 American kindreds previously described as affected only by trismus-pseudocamptodactyly syndrome (158300) (Mabry et al., 1974; Lefaivre and Aitchison, 2003), Veugelers et al. (2004) identified the R674Q mutation. Genealogic analyses to the year 1850 revealed no interrelationship between the 2 families, although both reported Dutch ancestry. Both families shared an extended haplotype of approximately 13 cM surrounding MYH8 exon 16. However, the Belgian family with Carney complex variant and trismus-pseudocamptodactyly syndrome originally reported by Chaudron et al. (1992) shared with the 2 American families a more restricted haplotype of only 2.7 kb surrounding exon 16. Thus, the Belgian family appeared to be more distantly related.
Toydemir et al. (2006) identified the R674Q mutation in all affected members of 4 families with trismus-pseudocamptodactyly syndrome, including descendants of the original Dutch family reported by Ter Haar and Van Hoof (1974) and 3 kindreds ascertained in the United States, including 1 previously reported by Chen et al. (1992). Analysis of haplotype sharing revealed that while each of the U.S. pedigrees shared the same MYH8 haplotype, this haplotype was not shared by the Dutch kindred. None of the affected individuals had multiple hyperpigmented macules or cardiac myxomas, and the R674Q mutation was not found in 49 unrelated cases of Carney complex who were negative for mutation in the PRKAR1A gene (188830). Toydemir et al. (2006) concluded that Dutch and U.S. pedigrees with trismus-pseudocamptodactyly syndrome do not share a founder mutation, and that R674Q rarely, if ever, causes Carney complex.
Minzer-Conzetti et al. (2008) identified heterozygosity for the R674Q mutation in a 20-year-old man with trismus-pseudocamptodactyly syndrome. The patient had craniofacial dysmorphism and widespread joint involvement, in addition to the characteristic trismus and pseudocamptodactyly found in the disorder. The authors stated that the findings in this patient broadened the phenotype associated with the R674Q mutation.
In 2 brothers with trismus-pseudocamptodactyly, Bonapace et al. (2010) identified heterozygosity for the R674Q mutation in the MYH8 gene. The mutation was not found in their unaffected parents or sister; the authors stated that their findings were most consistent with germline mosaicism, although a recurrent de novo mutation could not be excluded.
Bonapace, G., Ceravolo, F., Piccirillo, A., Duro, G., Strisciuglio, P., Concolino, D. Germline mosaicism for the c.2021G-A (p.arg674gln) mutation in siblings with trismus pseudocamptodactyly. Am. J. Med. Genet. 152A: 2898-2900, 2010. [PubMed: 20949528] [Full Text: https://doi.org/10.1002/ajmg.a.33671]
Chaudron, J. M., Jacques, J. M., Heller, F. R., Cheron, P., Luwaert, R. The myxoma syndrome: an unusual entity: a family study. Europ. Heart J. 13: 569-573, 1992. [PubMed: 1600999] [Full Text: https://doi.org/10.1093/oxfordjournals.eurheartj.a060216]
Chen, H., Fowler, M., Hogan, G. R., Lew, D., Herbst, J., Albright, J. Trismus-pseudocamptodactyly syndrome: report of a family and review of literature with special consideration of morphologic features of the muscles. Dysmorph. Clin. Genet. 6: 165-174, 1992.
Karsch-Mizrachi, I., Feghali, R., Shows, T. B., Leinwand, L. A. Generation of a full-length human perinatal myosin heavy chain cDNA. Gene 89: 289-294, 1990. [PubMed: 2373371] [Full Text: https://doi.org/10.1016/0378-1119(90)90020-r]
Lefaivre, J.-F., Aitchison, M. J. Surgical correction of trismus in a child with Hecht syndrome. Ann. Plast. Surg. 50: 310-314, 2003. [PubMed: 12800911] [Full Text: https://doi.org/10.1097/01.sap.0000046787.17899.83]
Mabry, C. C., Barnett, I. S., Hutcheson, M. W., Sorenson, H. W. Trismus pseudocamptodactyly syndrome; Dutch-Kentucky syndrome. J. Pediat. 85: 503-508, 1974. [PubMed: 4443857] [Full Text: https://doi.org/10.1016/s0022-3476(74)80453-1]
Minzer-Conzetti, K., Wu, E., Vargervik, K., Slavotinek, A. Phenotypic variation in trismus-pseudocamptodactyly syndrome caused by a recurrent MYH8 mutation. Clin. Dysmorph. 17: 1-4, 2008. [PubMed: 18049072] [Full Text: https://doi.org/10.1097/MCD.0b013e3282efdad8]
Soussi-Yanicostas, N., Whalen, R. G., Petit, C. Five skeletal myosin heavy chain genes are organized as a multigene complex in the human genome. Hum. Molec. Genet. 2: 563-569, 1993. [PubMed: 8518795] [Full Text: https://doi.org/10.1093/hmg/2.5.563]
Stratakis, C. A., Bertherat, J., Carney, J. A. Mutation of perinatal myosin heavy chain. (Letter) New Eng. J. Med. 351: 2556 only, 2004. [PubMed: 15590965] [Full Text: https://doi.org/10.1056/NEJM200412093512420]
Ter Haar, B. G. A., Van Hoof, R. F. The trismus-pseudocamptodactyly syndrome. J. Med. Genet. 11: 41-49, 1974. [PubMed: 4837286] [Full Text: https://doi.org/10.1136/jmg.11.1.41]
Toydemir, R. M., Chen, H., Proud, V. K., Martin, R., van Bokhoven, H., Hamel, B. C. J., Tuerlings, J. H., Stratakis, C. A., Jorde, L. B., Bamshad, M. J. Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8. Am. J. Med. Genet. 140A: 2387-2393, 2006. [PubMed: 17041932] [Full Text: https://doi.org/10.1002/ajmg.a.31495]
Veugelers, M., Bressan, M., McDermott, D. A., Weremowicz, S., Morton, C. C., Mabry, C. C., Lefaivre, J.-F., Zunamon, A., Destree, A., Chaudron, J.-M., Basson, C. T. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. New Eng. J. Med. 351: 460-469, 2004. [PubMed: 15282353] [Full Text: https://doi.org/10.1056/NEJMoa040584]
Weiss, A., Schiaffino, S., Leinwand, L. A. Comparative sequence analysis of the complete human sarcomeric myosin heavy chain family: implications for functional diversity. J. Molec. Biol. 290: 61-75, 1999. [PubMed: 10388558] [Full Text: https://doi.org/10.1006/jmbi.1999.2865]