A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFβ signaling and cause autosomal dominant spondylocarpotarsal synostosis

Abstract

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFβ signaling, revealing a regulatory role for embryonic myosin in the TGFβ signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

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

“…Given the recent implication of monoallelic MYH3 variants in some cases of SCTS 6,7 and the suspicion that recessive inheritance underpins SCTS in the families in this study, the maternally transmitted haplotypes in individuals 1 and 2 were also examined. This showed that the top maternally transmitted haplotype that individuals 1 and 2 shared with individual 5 was also inclusive of the MYH3 locus (a 9 cM segment encompassing 28 annotated genes; Figure 2B).…”

“…The wider cohort of SCTS-affected individuals without pathogenic variants in FLNB (n ¼ 16) had significantly more MYH3 truncating variants than presumptively healthy control individuals from publicly available databases (Supplemental Data). In the Genome Aggregation Database (gnomAD), 13 Our observations that individuals 1, 2, and 5 carry the same MYH3 splice-site variant on a shared paternal haplotype and also share a maternal haplotype in the context of 6 Zieba et al 7 Chong et al sibling recurrence suggest that a maternally derived pathogenic variant remains to be defined. We therefore performed WGS on individuals 1-3 and then prioritized and filtered MYH3 variants for high impact (SnpEff).…”

“…5 FLNB was the sole identified locus for SCTS until recent reports of monoallelic variants in MYH3 (MIM: 160720) in families affected by vertical transmission of a SCTS phenotype. 6 An unrelated individual with simplex SCTS and affected members of a three-generation family have also been reported to be heterozygous for protein-altering MYH3 mutations, 7 including an in-frame deletion of a single amino acid and a frameshift variant leading to a presumptive premature termination of protein translation. Before these observations, monoallelic missense MYH3 mutations transmitted in a dominant fashion were also shown to underlie cases of distal arthrogryposis type 8 (DA8, otherwise known as autosomal-dominant multiple pterygium syndrome [MIM: 178110]).…”

“…The implication of MYH3 in the etiopathogenesis of SCTS suggests functions that extend to osteogenesis, and indeed, Zieba et al have recently demonstrated its role in the regulation of TGFß activity in the scleromyotome; this role is reminiscent of the mechanism that underpins the FLNB-deficient form of the condition. 7 Here, we investigated the molecular basis of SCTS in a cohort of individuals with no FLNB variants accounting for their phenotypes. These individuals were phenotypically similar to those with SCTS caused by mutations in FLNB but with the notable exception of the presence of contractures that were often clinically prominent at birth.…”

Spondylocarpotarsal synostosis syndrome: “Bat wings” spinal fusions and “ladybug” carpal coalitions

“…2 Mutations in MYH3, which encodes embryonic myosin heavy chain 3, have been detected in some families with autosomal dominant SCT. 3 However, in some cases, the specific genetic mutation remains unknown. 2 Our patient underwent genetic study, with testing for mutation of the FLNB gene, but no specific genetic mutation could be demonstrated.…”