Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders

Abstract

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.

Spatial epigenome–transcriptome co-profiling of mammalian tissues

“…Epha5 (R6) is involved in axon guidance, whereas Slc1a3 (R8) is involved in regulation of excitatory neurotransmission in the CNS 18 . Myh3 (R3) is associated with muscle contraction 24 . Col2a1 (R7), which shows specific expression in cartilaginous tissues, has an essential role in normal embryonic skeleton development 18 .…”

Identification of two novel MYH3 variants causing different phenotypes in prenatal diagnosis

“…2 The variants leading to CPSFS1A and CPSFS1B are found to be located in any of the domains. 4 In the present study, the c.1024T>G (p.Phe342Val) variant of Fetus 1 is located within the head domain, and the c.3872A>C (p.Gln1291Pro) variant of Fetus 2 is located in the coiled-coil tail domain. Therefore, their phenotypes varied greatly.…”

“…The MYH3 variant is associated with distal arthrogryposis type 2A (Freeman‐Sheldon syndrome), distal arthrogryposis type 2B3 (Sheldon‐Hall syndrome), CPSFS1A (Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A) and CPSFS1B 2,3 . The diagnosis of MYH3 ‐associated disorders mainly depends on the clinical characteristics 4 . Sheldon‐Hall syndrome is the most common distal arthrogryposis, and Freeman‐Sheldon syndrome is one of the most severe distal arthrogryposes.…”

“…2,3 The diagnosis of MYH3-associated disorders mainly depends on the clinical characteristics. 4 Sheldon-Hall syndrome is the most common distal arthrogryposis, and Freeman-Sheldon syndrome is one of the most severe distal arthrogryposes. Both syndromes are autosomal dominant disorders and show camptodactyly and clubfeet, and it is difficult to distinguish between them.…”

Proteomics and Phosphoproteomics reveal Mechanism of Tuina in the Treatment of Frozen Shoulder：A research report based on rats

“…It is highly expressed during embryonic and fetal development, and is an important part of myo lament in skeletal muscle cell and non muscle cell 48 . Past researches has focused on the correlation between Myh3 with muscle-related disorders, but the role of Myh3 in FS has not been reported in studies 49 . This study found that Tuina can inhibit the capsule brosis through promoting Myh3 phosphorylation at S1916, S1148, S949 and T379, which indicated that Myh3 phosphorylation plays an important role in the mechanism of the treatment of Tuina therapy in FS.…”