Alternative titles; symbols
HGNC Approved Gene Symbol: MYH3
SNOMEDCT: 52616002, 771269000; ICD10CM: Q87.0;
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:10,628,532-10,678,417 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Arthrogryposis, distal, type 2A (Freeman-Sheldon) | 193700 | Autosomal dominant | 3 |
| Arthrogryposis, distal, type 2B3 (Sheldon-Hall) | 618436 | Autosomal dominant | 3 | |
| Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A | 178110 | Autosomal dominant | 3 | |
| Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B | 618469 | Autosomal recessive | 3 |
For background information on the myosin heavy chain genes, see MYH1 (160730).
In mammals at least 10 different myosin heavy chain (MHC) isoforms have been described from striated, smooth, and nonmuscle cells. These isoforms show expression that is spatially and temporally regulated during development. The hexameric myosin molecule consists of 2 heavy chains (200 kD each) and 2 pairs of light chains (16 to 20 kD each). The heavy chain can be divided into 2 domains, the globular amino terminal head responsible for binding to the myosin light chain and to actin as well as for ATP hydrolysis, and the alpha-helical carboxy terminal rod responsible for the ability of myosin to form filaments. In rats, Whalen et al. (1979) identified fast- and slow-type myosin heavy chains in adult muscle; embryonic muscle had a distinct form. Expression of embryonic MHC is a hallmark of muscle regeneration after birth and a characteristic marker of human muscular dystrophies. During normal human development, expression is restricted to the embryonic period of development. In primary human muscle cell cultures devoid of other cell types, the embryonic MHC gene is active during the first 10 days with a peak at 2 days after the onset of formation of myotubes; thus, embryonic development is recapitulated (Karsch-Mizrachi et al., 1989).
Chong et al. (2015) tested for MYH3 expression in a variety of human fetal tissues and observed expression in thymus, placenta, heart, and liver. MYH3 expression was not detectable in cartilage, but it was detected in bone. Furthermore, qPCR assay confirmed MYH3 expression in bone at levels comparable to those in several other tissues with known MYH3 expression, including brain.
Zieba et al. (2017) analyzed expression of Myh3 in wildtype mouse spine sagittal sections at embryonic day (E) 15.5 and postnatal days (P) 1 and 15. Immunohistochemical staining confirmed that embryonic myosin is expressed in bone. Myh3 showed high expression in the small multifidus muscles that attach at the distal neural arches of the spine at E15.5 and P1, with slightly lower levels at P15. There was no expression of embryonic myosin within the annulus fibrosus or nucleus pulposus at any age, a finding that was confirmed by RT-PCR.
Eller et al. (1989) mapped the embryonic myosin heavy chain gene to chromosome 17 by Southern blot analysis of somatic cell hybrid DNAs.
Yoon et al. (1992) identified a cluster of skeletal myosin heavy chain genes, including MYH3, on chromosome 17p13.
Distal Arthrogryposis, Types DA2A and DA2B3
Toydemir et al. (2006) screened 28 Freeman-Sheldon syndrome (FSS, or DA2A; 193700) probands (7 familial and 21 sporadic) for mutations in genes that encode myosin heavy chains. In 26 of 28 FSS cases, they found mutations (e.g., 160720.0001-160720.0004) in the MYH3 gene. The disorder is also known as distal arthrogryposis 2A. Because children with FSS and Sheldon-Hall syndrome (SHS; see DA2B3, 618436) have similar phenotypic characteristics, Toydemir et al. (2006) screened the MYH3 gene in 38 independent cases of SHS in whom no mutation in TNNI2 (191043) or TNNT3 (600692) had been found. They found MYH3 mutations in 5 (42%) of 12 familial and 7 (27%) of 26 sporadic cases, or 12 (32%) of 38 total cases. Two individuals with SHS (1 sporadic and 1 familial case) had a 3-bp deletion (160720.0005) of the MYH3 gene, whereas all the remaining cases had missense mutations (e.g., 160720.0006) predicted to affect highly conserved amino acid residues. None of the SHS patients had 1 of the common arg672 substitutions (160720.0001 and 160720.0002) that cause FSS, and only 1 mutation (T178I; 160720.0004) was shared between FSS and SHS patients. Most of the amino acid substitutions that cause FSS or SHS localized to the head domain of myosin. However, in contrast to substitutions causing FSS, none of the amino acid residues disturbed in SHS mapped to the groove near the ATP binding site of myosin. Instead, Toydemir et al. (2006) found that amino acid substitutions that cause SHS localized primarily to surfaces that were hypothesized to interact with other proteins of the contractile apparatus such as actin (ACTA1; 102610) and troponin (see 600692), consistent with the observation that mutations in the ACTA1, TNNI2, and TNNT3 genes also cause contractures.
In affected members of 2 unrelated families with DA2B3 and a patient with sporadic DA2A, Tajsharghi et al. (2008) identified 3 different heterozygous missense mutations in the MYH3 gene (160720.0003, 160720.0007-160720.0008), occurring within or adjacent to the ATP-binding pocket of the protein and suggesting that they may disrupt ATP binding or hydrolysis. Some of the patients reported muscle weakness, and skeletal muscle biopsies showed mild pathologic changes with small and frequent type 1 fibers. No MYH3 protein was detected, consistent with normal developmental downregulation. Tajsharghi et al. (2008) suggested that distal arthrogryposis associated with MYH3 mutations may cause a severe myopathy during fetal development, resulting in congenital joint contractures, with residual muscle defects that manifest as a myopathy after embryonic myosin is downregulated postnatally.
In affected members of a 4-generation Chinese family with type 2B distal arthrogryposis, Xu et al. (2018) identified heterozygosity for a missense mutation in the MYH3 gene (Y387C; 160720.0012) that segregated fully with disease and was not found in the ExAC database.
Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A
By exome sequencing in 3 multigenerational families in which affected individuals exhibited contractures, pterygia, and vertebral fusions (CPSFS1A; 178110) and were negative for mutation or copy number variation in 6 candidate genes, Chong et al. (2015) identified heterozygous mutations in the MYH3 gene (160720.0009-160720.0011) that segregated with disease in the respective families. All 3 mutations involved highly conserved residues and were not found in public databases. Chong et al. (2015) noted that affected individuals have multiple pterygia of the limbs, severe scoliosis, and vertebral fusions, but do not display contractures of the facial muscles as observed in patients with distal arthrogryposes.
In a French mother and son (family 1) with limited joint mobility and vertebral and carpal fusions, previously studied by Isidor et al. (2008) and found to be negative for mutation in the FLNB (603381) and NOG (602991) genes, Carapito et al. (2016) performed exome sequencing and identified heterozygosity for a missense mutation in the MYH3 gene (T333R; 160720.0013). An unrelated mother and daughter (family 2) with multiple pterygia and vertebral, carpal, and tarsal fusions were found to be heterozygous for a different missense mutation in MYH3 (L1344P; 160720.0014). The mutations segregated with disease and were not found in public variant databases.
By exome sequencing in 3 probands from the International Skeletal Dysplasia Registry with vertebral, carpal, and tarsal fusions, Zieba et al. (2017) identified heterozygosity for mutations in the MYH3 gene (see, e.g., 160720.0011). Functional analysis showed reduced TGF-beta signaling (see 190180) with all 3 mutations.
In an 8.5-year-old Italian boy with multiple joint contractures and facial dysmorphism reminiscent of DA2B3, as well as wide neck, mild scoliosis, and vertebral and carpal fusions, who was negative for mutation in Noonan syndrome (see 163950)-associated genes, Scala et al. (2018) sequenced the MYH3 gene and identified heterozygosity for a missense mutation (F287V; 160720.0015).
From a cohort of 16 patients with multiple contractures and pterygia as well as vertebral fusions and variable carpal and/or tarsal fusions, who were known to be negative for mutation in the FLNB gene, Cameron-Christie et al. (2018) identified 4 patients from 3 families with heterozygous mutations in the MYH3 gene (see, e.g., 160720.0016).
Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1B
From a cohort of 16 patients with multiple contractures and pterygia as well as vertebral fusions and variable carpal and/or tarsal fusions, who were known to be negative for mutation in the FLNB gene, Cameron-Christie et al. (2018) identified 6 patients from 4 unrelated families (see CPSFS1B, 618469) who were compound heterozygous for mutations in the MYH3 gene (see, e.g., 160720.0017-160720.0020). The second mutation in all patients was a noncoding variant at a splice donor site flanking a noncoding exon in the 5-prime UTR of MYH3 (160720.0020), which the authors noted would not be detected by most clinical exome-capture programs.
Cameron-Christie et al. (2018) stated that some genotype-phenotype correlations in the distal arthrogryposes had been established, with mutations associated with a DA1 (DA1A; 108120)-like phenotype involving residues located in the head of MYHC-Emb, and those causing DA2A typically lying close to a groove between 2 parts of the ATP binding site. Mutations causing DA2B3 affect the head, neck, or hinge of MYHC-Emb and mostly lie near the surface of the protein. However, the authors noted that there is a high degree of phenotypic variability such that individuals with the same mutation can be mildly or severely affected, and are sometimes clinically diagnosed with a different type of DA.
In 12 patients with Freeman-Sheldon syndrome (DA2A; 193700), Toydemir et al. (2006) identified a 2084G-A transition in exon 17 of the MYH3 gene, resulting in an arg672-to-his (R672H) substitution that was predicted to affect ATP binding.
In 8 patients with Freeman-Sheldon syndrome (DA2A; 193700), Toydemir et al. (2006) identified a 2083C-T transition in exon 17 of the MYH3 gene, resulting in an arg672-to-cys (R672C) substitution that was predicted to affect ATP binding.
In 3 patients with the Freeman-Sheldon syndrome (DA2A; 193700) and 2 patients with Sheldon-Hall syndrome (DA2B3; 618436), Toydemir et al. (2006) identified a 602C-T transition in exon 5 of the MYH3 gene, resulting in a thr178-to-ile (T178I) substitution that was predicted to affect ATP binding.
In a 5-year-old patient with sporadic distal arthrogryposis type 2A (DA2A), Tajsharghi et al. (2008) identified heterozygosity for the same T178I mutation in MYH3. They noted that this residue is adjacent to the base of the ATP-binding pocket known as the phosphate-binding loop. The patient had ptosis, very short stature, small contracted mouth, and proximal and distal joint contractures. Muscle biopsies showed no MYH3 expression, consistent with normal developmental downregulation. However, at age 15 months, muscle biopsy showed increased expression of fetal MYH8 (160741), but this had disappeared by age 5 years. (The original article by Tajsharghi et al. (2008) erroneously stated that the mutation was THR178MET.)
In a sporadic case of Freeman-Sheldon syndrome (DA2A; 193700), Toydemir et al. (2006) identified a 2543T-A transversion in exon 21 of the MYH3 gene, resulting in a val825-to-asp (V825D) substitution that was predicted to alter association with the regulatory light chain of the actin-myosin complex. This was the only one of 6 different missense mutations causing Freeman-Sheldon syndrome that was not located close to a groove that is a prominent feature of the myosin head.
In 1 sporadic and 1 familial patient with Sheldon-Hall syndrome (DA2B3; 618436), Toydemir et al. (2006) identified a 3-bp deletion (2590_2592delCTC) in exon 21 of the MYH3 gene, predicted to remove leu841.
In a patient with Sheldon-Hall syndrome (DA2B3; 618436), Toydemir et al. (2006) identified an 1192G-A transition in exon 11 of the MYH3 gene, resulting in a glu375-to-lys (E375K) substitution.
In a mother and daughter with distal arthrogryposis type 2B (DA2B3; 618436), Tajsharghi et al. (2008) identified a heterozygous 1454A-G transition in exon 13 of the MYH3 gene, resulting in asp462-to-gly (D462G) substitution in a highly conserved residue near regions important for ATP binding and hydrolysis. Clinical features included short stature, scoliosis, mild facial dysmorphism, decreased muscle strength, and contractures of the proximal and distal joints. Muscle biopsies also showed mild pathologic changes, including increased fiber size variability, small type 1 fibers, and predominance of type 1 fibers. Muscle biopsies showed no MYH3 expression, consistent with normal developmental downregulation.
In a man and his 3 children with a mild form of distal arthrogryposis type 2B (DA2B3; 618436), Tajsharghi et al. (2008) identified a heterozygous 769C-T transition in exon 7 of the MYH3 gene, resulting in an ala234-to-thr (A234T) substitution. This residue is highly conserved in other MYH isoforms and is located close to the helix that forms part of the nucleotide-binding pocket in the S1 domain. The proband had contractures primarily in the hands, with mild involvement of the jaw, feet, and elbows. Muscle biopsies showed no MYH3 expression, consistent with developmental downregulation.
In a father and 2 daughters who exhibited contractures, pterygia, and vertebral fusions (CPSFS1A; 178110), Chong et al. (2015) identified heterozygosity for a 3-bp duplication (c.3214_3216dup, NM_002470.3) in exon 25 of the MYH3 gene, resulting in duplication of a highly conserved asparagine residue (asn1072dup). The duplication segregated with disease in the family and was not found in more than 71,000 control exomes, including more than 1,400 in-house chromosomes and those recorded in the Exome Variant Server (ESP6500), 1000 Genomes Project (Phase 1), and ExAC databases.
In a father and daughter who exhibited contractures, pterygia, and vertebral fusions (CPSFS1A; 178110), Chong et al. (2015) identified heterozygosity for a c.3224A-C transversion (c.3224A-C, NM_002470.3) in exon 25 of the MYH3 gene, resulting in a gln1075-to-pro (Q1075P) substitution at a highly conserved residue. The mutation segregated with disease in the family and was not found in more than 71,000 control exomes, including more than 1,400 in-house chromosomes and those recorded in the Exome Variant Server (ESP6500), 1000 Genomes Project (Phase 1), and ExAC databases.
In an affected mother and son and a maternal grandfather from a large 5-generation family in which 10 individuals exhibited contractures, pterygia, and vertebral fusions (CPSFS1A; 178110), Chong et al. (2015) identified heterozygosity for a 3-bp deletion (c.727_729del, NM_002470.3) in exon 8 of the MYH3 gene, resulting in deletion of a highly conserved serine residue (ser243del). The deletion, which segregated with disease in the family, was not found in the Exome Variant Server (ESP6500), 1000 Genomes Project, or ExAC databases.
In a woman (R07-183B) with mild short stature, short neck, limited elbow extension, finger webbing, severe scoliosis, and vertebral, carpal, and tarsal fusions, Zieba et al. (2017) identified heterozygosity for the in-frame 3-bp deletion (c.727_729delTCC), resulting in deletion of ser243. The proband was a member of a large family (R07-183) segregating the disorder in an autosomal dominant pattern: she had an affected son, brother, father, and 2 paternal uncles, most of whom reported only scoliosis and vertebral fusions, with mild hand contractures in some. Mutation status for the proband's family members was not reported. Western blot analysis of protein samples from transfected HEK cells showed production of a full-length protein; however, it was less stable than wildtype MYH3, and functional analysis showed decreased activation of both canonical and noncanonical TGF-beta (see 190180) signaling with the mutant compared with wildtype MYH3.
In 6 affected members over 3 generations of a large Chinese family with distal arthrogryposis type 2B3 (DA2B3; 618436), Xu et al. (2018) identified heterozygosity for a c.1160A-G transition in the MYH3 gene, resulting in a tyr387-to-cys (Y387C) substitution at a highly conserved residue. The mutation was not found in 4 unaffected family members, 250 Chinese controls, or in the ExAC database. Marked intrafamilial phenotypic variation was observed in this family, in which 3 affected individuals exhibited primarily facial dysmorphism.
In a French mother and son (family 1) with joint mobility limitations and vertebral and carpal fusions (CPSFS1A; 178110), originally reported by Isidor et al. (2008), Carapito et al. (2016) identified heterozygosity for a c.998C-G transversion (c.998C-G, NM_002470.3) in exon 11 of the MYH3 gene, resulting in a thr333-to-arg (T333R) substitution in the head domain. The mutation, which was shown to have arisen de novo in the mother, segregated fully with disease in the family and was not found in 200 in-house exomes or in the ESP6500, 1000 Genomes Project, or ExAC databases.
In a mother and daughter (family 2) with contractures, pterygia, and vertebral, carpal, and tarsal fusions (CPSFS1A; 178110), Carapito et al. (2016) identified heterozygosity for a c.4031T-C transition (c.4031T-C, NM_002470.3) in exon 30 of the MYHC gene, resulting in a leu1344-to-pro (L1344P) substitution in the protein tail. The mutation was not found in the unaffected father, in 200 in-house exomes, or in the ESP6500, 1000 Genomes Project, or ExAC databases.
In an 8.5-year-old Italian boy with multiple joint contractures, wide neck, and vertebral and carpal fusions (CPSFS1A; 178110), Scala et al. (2018) identified heterozygosity for a c.859T-G transversion in exon 10, resulting in a phe287-to-val (F287V) substitution at a highly conserved residue within the head domain. The authors noted that this patient exhibited facial dysmorphism that showed overlap with DA2B3 (618436).
In 2 Dutch sisters (family 2) with finger contractures, webbing of the neck and fingers, and vertebral, carpal, and tarsal fusions (CPSFS1A; 178110), Cameron-Christie et al. (2018) identified heterozygosity for a splicing mutation (c.1581+1G-A, NM_002470.3) in the MYH3 gene. The mutation was inherited from their mother, who exhibited only camptodactyly.
In 2 Dutch sisters (family 1) and an unrelated Dutch female patient (family 3) with multiple contractures, variable pterygia, and variable skeletal fusions (CPSFS1B; 618469), Cameron-Christie et al. (2018) identified compound heterozygosity for splicing variants in the MYH3 gene: a c.4647+1G-A transition (c.4647+1G-A, NM_002470.3) and a c.-9+1G-A transition (160720.0020). Initial analysis of exome sequencing and haplotype data had demonstrated that the c.4647+1G-A variant was carried on a shared paternal haplotype in all 3 patients; the detection of a shared maternal haplotype, a 23-cM segment overlapping 212 genes, including MYH3, resulted in whole-genome sequencing and the detection of the second splicing variant (c.-9+1G-A) on the maternal haplotype.
In a North African woman (individual 6) with contractures of the elbows, knees, and hips, webbing of the neck, and vertebral fusions (CPSFS1B; 618469), Cameron-Christie et al. (2018) identified compound heterozygosity for a c.141T-G transversion (c.141T-G, NM_002470.3) in the MYH3 gene, resulting in a tyr47-to-ter (Y47X) substitution, and a splicing mutation (c.-9+1G-A; 160720.0020).
In a Bangladeshi brother and sister (family 4) with contractures, variable webbing, and vertebral fusions but no carpotarsal fusions (CPSFS1B; 618469), Cameron-Christie et al. (2018) identified compound heterozygosity for a 6-kb intragenic deletion beginning within intron 12 and continuing to partway through exon 26, and a splicing mutation (c.-9+1G-A; 160720.0020). The deletion was inherited from their unaffected father.
In 6 patients from 4 families (families 1, 3, and 4, and individual 6) with contractures, pterygia, and variable skeletal fusions (CPSFS1B; 618469), Cameron-Christie et al. (2018) identified compound heterozygosity for mutations in the MYH3 gene. The first mutation included a splicing variant (160720.0017), a nonsense mutation (160720.0018), and a deletion (160720.0019). The second mutation in all 6 patients was a splicing variant (c.-9+1G-A, NM_002470.3) in the 5-prime UTR, involving the canonical donor splice site at the untranslated boundary between exon 2 and intron 2. The authors noted that the first 2 exons of MYH3, including the site of the c.-9+1G-A variant, are not covered by commonly used exome sequencing capture platforms. This variant was present in 2 of 2,535 individuals in the 1000 Genomes Project and 85 heterozygous individuals in gnomAD (allele frequency, 0.003). Analysis of transfected HEK293FT cells showed splicing inclusive of exons 1 to 3 in 71% of transcripts (splice form A) with wildtype MYH3, with 25% showing skipping of exon 2 (splice form B), whereas with the mutant, the predominant transcript was splice form B, with only negligible amounts of splice form A, and 35% of transcripts represented a third splice variant that used a cryptic splice donor site 13 bp 5-prime of the canonical site (splice form C). Functional analysis demonstrated that splice form B, the predominant splice form with the rs557849165 mutant, had a translational efficiency of 54% compared to wildtype.
Cameron-Christie, S. R., Wells, C. F., Simon, M., Wessels, M., Tang, C. Z. N., Wei, W., Takei, R., Aarts-Tesselaar, C., Sandaradura, S., Sillence, D. O., Cordier, M.-P,, Veenstra-Knol, H. E., Cassina, M., Ludkig, K., Trevission, E., Bahlo, M., Markie, D. M., Jenkins, Z. A., Robertson, S. P. Recessive spondylocarpotarsal synostosis syndrome due to compound heterozygosity for variants in MYH3. Am. J. Hum. Genet. 102: 1115-1125, 2018. Note: Erratum: Am. J. Hum. Genet. 105: 669 only, 2019. [PubMed: 29805041] [Full Text: https://doi.org/10.1016/j.ajhg.2018.04.008]
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Zieba, J., Zhang, W., Chong, J. X., Forlenza, K. N., Martin, J. H., Heard, K., Grange, D. K., Butler, M. G., Kleefstra, T., Lachman, R. S., Nickerson, D., Regnier, M., Cohn, D. H., Bamshad, M., Krakow, D. A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGF-beta signaling and cause autosomal dominant spondylocarpotarsal synostosis. Sci. Rep. 7: 41803, 2017. Note: Electronic Article. [PubMed: 28205584] [Full Text: https://doi.org/10.1038/srep41803]