Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3

Cameron-Christie, Sophia R.; Wells, Constance; Simon, Marleen; Wessels, Marja W.; Tang, Candy Z.N.; Wei, Wenhao; Takei, Riku; Aarts-Tesselaar, Coranne; Sandaradura, Sarah A.; Sillence, David; Cordier, Marie Pierre; Veenstra‐Knol, Hermine E.; Cassina, Matteo; Ludwig, Kathrin; Trevisson, Eva; Bahlo, Melanie; Markie, David; Jenkins, Zandra A.; Robertson, Stephen

doi:10.1016/j.ajhg.2019.08.007

Cited by 4 publications

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“…Because of the dimerization of the myosin heavy chains, and subsequent assembly of the hexamers into the thick filament, it is reasonable to hypothesize that compound heterozygosity of a missense mutation in trans with a hypomorphic or null allele will increase the phenotypic severity of afflicted individuals compared to a missense mutation in trans with a wild‐type allele. In fact, a Dutch study recently identified a high impact MYH3 5′ UTR variant with a gnomAD minor allele frequency of 0.008 that diminishes MYH3 translational efficiency (Cameron‐Christie et al , 2018). This variant was reported in patients with presumed autosomal recessive spondylocarpotarsal synostosis syndrome, demonstrating a biallelic phenotype consisting of a haploinsufficient allele and a hypomorphic allele.…”

Section: Discussionmentioning

confidence: 99%

“…The phenotypic spectrum of MYH3 ‐associated disease was recently broadened to include vertebral fusions, which are a defining clinical feature of spondylocarpotarsal synostosis syndrome. Spondylocarpotarsal synostosis syndrome is associated with both autosomal dominant and recessive inheritance; both missense and nonsense MYH3 variants have been reported in recessive cases (Carapito et al , 2016; Zieba et al , 2017; Cameron‐Christie et al , 2018). Congenital spinal fusions were observed in our smyhc1 R673H mutants but not in smyhc1 null mutant fish, suggesting that bony fusions in our missense model result secondarily from increased tension generated by the mutant muscle protein, putting excessive tension and stress on the notochord, causing it to kink.…”

Section: Discussionmentioning

confidence: 99%

“…The most common genetic causes of DA are autosomal dominant missense mutations in the MYH3 gene, encoding the embryonic myosin heavy chain (MyHC) that is expressed first during slow skeletal muscle development. MYH3 expression peaks during fetal development, and is significantly downregulated after birth (Chong et al , 2015; Schiaffino et al , 2015; Cameron‐Christie et al , 2018). MYH3 mutations have been identified in multiple DA syndromes, including distal arthrogryposis, type 1 (Alvarado et al , 2011), DA2A, and distal arthrogryposis type 2B (DA2B) (also called Sheldon‐Hall syndrome) (Toydemir et al , 2006; Beck et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

“…MYH3 mutations have been identified in multiple DA syndromes, including distal arthrogryposis, type 1 (Alvarado et al , 2011), DA2A, and distal arthrogryposis type 2B (DA2B) (also called Sheldon‐Hall syndrome) (Toydemir et al , 2006; Beck et al , 2013). MYH3 mutations have additionally been identified in patients with multiple pterygium syndrome (Chong et al , 2015), and spondylocarpotarsal synostosis syndrome, which is associated with vertebral, carpal, and tarsal fusions in addition to joint contractures (Carapito et al , 2016; Zieba et al , 2017; Cameron‐Christie et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The functional effects of DA‐associated MYH3 missense mutations include slowing the muscle relaxation time and prolonging the muscle fiber contracted state (Racca et al , 2015; Walklate et al , 2016). While the vast majority of described DA mutations are dominant missense variants, the recent identification of autosomal recessive MYH3 variants in spondylocarpotarsal synostosis syndrome suggests that some mutations may also contribute to disease pathogenesis through a loss of function or hypomorphic mechanism (Cameron‐Christie et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

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MYH 3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin

et al. 2020

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Distal arthrogryposis (DA) is group of syndromes characterized by congenital joint contractures. Treatment development is hindered by the lack of vertebrate models. Here, we describe a zebrafish model in which a common MYH3 missense mutation (R672H) was introduced into the orthologous zebrafish gene smyhc1 (slow myosin heavy chain 1) (R673H). We simultaneously created a smyhc1 null allele (smyhc1−), which allowed us to compare the effects of both mutant alleles on muscle and bone development, and model the closely related disorder, spondylocarpotarsal synostosis syndrome. Heterozygous smyhc1R673H/+ embryos developed notochord kinks that progressed to scoliosis with vertebral fusions; motor deficits accompanied the disorganized and shortened slow‐twitch skeletal muscle myofibers. Increased dosage of the mutant allele in both homozygous smyhc1R673H/R673H and transheterozygous smyhc1R673H/− embryos exacerbated the notochord and muscle abnormalities, causing early lethality. Treatment of smyhc1R673H/R673H embryos with the myosin ATPase inhibitor, para‐aminoblebbistatin, which decreases actin–myosin affinity, normalized the notochord phenotype. Our zebrafish model of MYH3‐associated DA2A provides insight into pathogenic mechanisms and suggests a beneficial therapeutic role for myosin inhibitors in treating disabling contractures.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MYH 3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin

et al. 2020

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Recessive MYH3 variants cause “Contractures, pterygia, and variable skeletal fusions syndrome 1B” mimicking Escobar variant multiple pterygium syndrome

Hakonen

Lehtonen

Kivirikko

et al. 2020

American J of Med Genetics Pt A

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The multiple pterygium syndromes (MPS) are rare disorders with disease severity ranging from lethal to milder forms. The nonlethal Escobar variant MPS (EVMPS) is characterized by multiple pterygia and arthrogryposis, as well as various additional features including congenital anomalies. The genetic etiology of EVMPS is heterogeneous and the diagnosis has been based either on the detection of pathogenic CHRNG variants (23% of patients), or suggestive clinical features. We describe four patients with a clinical suspicion of EVMPS who manifested with multiple pterygia, mild flexion contractures of several joints, and vertebral anomalies. We revealed recessively inherited MYH3 variants as the underlying cause in all patients: two novel variants, c.1053C>G, p.(Tyr351Ter) and c.3102+5G>C, as compound heterozygous with the hypomorphic MYH3 variant c.-9+1G>A. Recessive MYH3 variants have been previously associated with spondylocarpotarsal synostosis syndrome. Our findings now highlight multiple pterygia as an important feature in patients with recessive MYH3 variants. Based on all patients with recessive MYH3 variants reported up to date, we consider that this disease entity should be designated as "Contractures, pterygia, and variable skeletal fusions syndrome 1B," as recently suggested by OMIM. Our findings underline the importance of analyzing MYH3 in the differential diagnosis of EVMPS, particularly as the hypomorphic MYH3 variant might remain undetected by routine exome sequencing.

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LncRNA-FKBP1C regulates muscle fiber type switching by affecting the stability of MYH1B

Wang

Yang

et al. 2021

Cell Death Discov.

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Long non-coding RNAs (lncRNAs) are well-known to participate in a variety of important regulatory processes in myogenesis. In our previous RNA-seq study (accession number GSE58755), we found that lncRNA-FKBP1C was differentially expressed between White Recessive Rock (WRR) and Xinghua (XH) chicken. Here, we have further demonstrated that lncRNA-FKBP1C interacted directly with MYH1B by biotinylated RNA pull-down assay and RNA immunoprecipitation (RIP). Protein stability and degradation experiments identified that lncRNA-FKBP1C enhanced the protein stability of MYH1B. Overexpression of lncRNA-FKBP1C inhibited myoblasts proliferation, promoted myoblasts differentiation, and participated in the formation of skeletal muscle fibers. LncRNA-FKBP1C could downregulate the fast muscle genes and upregulate slow muscle genes. Conversely, its interference promoted cell proliferation, repressed cell differentiation, and drove the transformation of slow-twitch muscle fibers to fast-twitch muscle fibers. Similar results were observed after knockdown of the MYH1B gene, but the difference was that the MYH1B gene had no effects on fast muscle fibers. In short, these data demonstrate that lncRNA-FKBP1C could bound with MYH1B and enhance its protein stability, thus affecting proliferation, differentiation of myoblasts and conversion of skeletal muscle fiber types.

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Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3

Cited by 4 publications

References 0 publications

MYH 3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin

MYH 3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin

Recessive MYH3 variants cause “Contractures, pterygia, and variable skeletal fusions syndrome 1B” mimicking Escobar variant multiple pterygium syndrome

LncRNA-FKBP1C regulates muscle fiber type switching by affecting the stability of MYH1B

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