Bi-allelic MYH3 loss-of-function variants cause a lethal form of contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B

Kamien, Benjamin; Clayton, Joshua S.; Lee, Han‐Shin; Abeysuriya, Disna; McNamara, Elyshia; Martinovic, Jéléna; Gonzalès, Marie; Melki, Judith; Ravenscroft, Gianina

doi:10.1016/j.nmd.2022.03.007

Cited by 2 publications

(4 citation statements)

References 16 publications

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“…In this study, we characterize the musculoskeletal defects seen in Myh3 knockout mice during adult stages. Although missense mutations in MYH3 lead to several monoallelic musculoskeletal diseases such as Freeman–Sheldon syndrome, Sheldon–Hall syndrome, and multiple pterygium syndrome, the disorder where MYH3 mutations lead to partial or total loss of MyHC‐embryonic function is spondylocarpotarsal synostosis (Cameron‐Christie et al , 2018 ; Whittle et al , 2021 ; Kamien et al , 2022 ). Hence, the germline knockout Myh3 mice serve as the first mammalian animal model to study MYH3 ‐associated SCTS.…”

Section: Discussionmentioning

confidence: 99%

“…Later studies confirmed this by generating a mouse knockout for Flnb , which exhibited similar abnormalities as seen in human patients with SCTS (Farrington‐Rock et al , 2008 ). More recently, dominant and recessive MYH3 mutations have been reported to lead to SCTS (Carapito et al , 2016 ; Cameron‐Christie et al , 2018 ; Kamien et al , 2022 ). Both FLNB and MyHC‐embryonic have been reported to alter transforming growth factor‐β (TGF‐β) signaling in SCTS, suggesting that they might function through conserved pathways (Zieba et al , 2016 , 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent studies have started to identify recessive MYH3 mutations in the compound heterozygous condition, which lead to SCTS (Cameron‐Christie et al , 2018 ). A recent case study reports that homozygous or compound heterozygous MYH3 mutations resulting in near‐complete to total loss of function of MyHC‐embryonic in three fetuses led to SCTS‐like phenotypes with fetal lethality (Kamien et al , 2022 ). This suggests that MYH3 ‐associated SCTS most likely results from the loss of function of MyHC‐embryonic rather than dominant mutations that alter its contractile properties.…”

Section: Introductionmentioning

confidence: 99%

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Musculoskeletal defects associated with myosin heavy chain‐embryonic loss of function are mediated by the YAP signaling pathway

et al. 2023

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Mutations in MYH3, the gene encoding the developmental myosin heavy chain‐embryonic (MyHC‐embryonic) skeletal muscle‐specific contractile protein, cause several congenital contracture syndromes. Among these, recessive loss‐of‐function MYH3 mutations lead to spondylocarpotarsal synostosis (SCTS), characterized by vertebral fusions and scoliosis. We find that Myh3 germline knockout adult mice display SCTS phenotypes such as scoliosis and vertebral fusion, in addition to reduced body weight, muscle weight, myofiber size, and grip strength. Myh3 knockout mice also exhibit changes in muscle fiber type, altered satellite cell numbers and increased muscle fibrosis. A mass spectrometric analysis of embryonic skeletal muscle from Myh3 knockouts identified integrin signaling and cytoskeletal regulation as the most affected pathways. These pathways are closely connected to the mechanosensing Yes‐associated protein (YAP) transcriptional regulator, which we found to be significantly activated in the skeletal muscle of Myh3 knockout mice. To test whether increased YAP signaling might underlie the musculoskeletal defects in Myh3 knockout mice, we treated these mice with CA3, a small molecule inhibitor of YAP signaling. This led to increased muscle fiber size, rescue of most muscle fiber type alterations, normalization of the satellite cell marker Pax7 levels, increased grip strength, reduced fibrosis, and decline in scoliosis in Myh3 knockout mice. Thus, increased YAP activation underlies the musculoskeletal defects seen in Myh3 knockout mice, indicating its significance as a key pathway to target in SCTS and other MYH3‐related congenital syndromes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Musculoskeletal defects associated with myosin heavy chain‐embryonic loss of function are mediated by the YAP signaling pathway

et al. 2023

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“…Patients with this disorder often exhibit significant scoliosis and limited mobility. To date, only six studies with less than 20 patients involving with CPSF1B have been reported (Cameron‐Christie et al., 2018 ; Dahan‐Oliel et al., 2021 ; Hakonen et al., 2020 ; Kamien et al., 2022 ; Thiffault et al., 2019 ; Zhao et al., 2022 ), which keeps the characteristic spectrum, natural clinical course, and pathogenesis of this disease still far from well‐known.…”

Section: Introductionmentioning

confidence: 99%

Functional assessment of a novel biallelic MYH3 variation causing CPSKF1B (contractures, pterygia, and spondylocarpotarsal fusion syndrome1B)

He,

Wu,

Sun

et al. 2024

Molec Gen & Gen Med

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BackgroundThe MYH3‐associated myosinopathies comprise a spectrum of rare neuromuscular disorders mainly characterized by distal arthrogryposis with or without other features like pterygia and vertebrae fusion. CPSKF1B (contractures, pterygia, and spondylocarpotarsal fusion syndrome1B) is the only known autosomal recessiveMYH3‐associated myosinopathy so far, with no more than two dozen cases being reported.Materials and MethodsA boy with CPSKF1B was recruited and subjected to a comprehensive clinical and imaging evaluation. Genetic detection with whole‐exome sequencing (WES) was performed on the patient and extended family members to identify the causative variation. A series of in silico and in vitro investigations were carried out to verify the pathogenicity of the two variants of the identified compound heterozygous variation.ResultsThe patient exhibited moderate CPSKF1B symptoms including multiarticular contractures, webbed neck, and spondylocarpotarsal fusion. WES detected a compound heterozygous MYH3 variation consisting of two variants, namely NM_002470.4: c.3377A>G; p. (E1126G) and NM_002470.4: c.5161‐2A>C. It was indicated that the NM_002470.4: c.3377A>G; p. (E1126G) variant mainly impaired the local hydrogen bond formation and impacted the TGF‐B pathway, while the NM_002470.4: c.5161‐2A>C variant could affect the normal splicing of pre‐mRNA, resulting in the appearance of multiple abnormal transcripts.ConclusionsThe findings of this study expanded the mutation spectrum of CPSKF1B, provided an important basis for the counseling of the affected family, and also laid a foundation for the functional study of MYH3 mutations.

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Bi-allelic MYH3 loss-of-function variants cause a lethal form of contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B

Cited by 2 publications

References 16 publications

Musculoskeletal defects associated with myosin heavy chain‐embryonic loss of function are mediated by the YAP signaling pathway

Musculoskeletal defects associated with myosin heavy chain‐embryonic loss of function are mediated by the YAP signaling pathway

Functional assessment of a novel biallelic MYH3 variation causing CPSKF1B (contractures, pterygia, and spondylocarpotarsal fusion syndrome1B)

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