Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome

Carapito, Raphaël; Goldenberg, Alice; Paul, Nicodéme; Pichot, Angélique; David, Albert; Hamel, Antoine; Dumant-Forest, Clémentine; Leroux, J.; Ory, Benjamin; Isidor, Bertrand; Bahram, Seiamak

doi:10.1038/ejhg.2016.84

Cited by 24 publications

(41 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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).…”

Section: Analysis Of Shared Haplotypesmentioning

confidence: 99%

“…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]).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Cameron-Christie

Wells

Simon

et al. 2018

The American Journal of Human Genetics

View full text Add to dashboard Cite

Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.

show abstract

Section: Analysis Of Shared Haplotypesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cameron-Christie

Wells

Simon

et al. 2018

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…Two families have been reported with autosomal dominant SCT due to variants in MYH3. 3 One family had pure SCT whereas the other family had additional features like joint limitation with pterygia and cardiac disease. However, further clinical and molecular information would be required to describe MYH3-related SCT.…”

Section: Discussionmentioning

confidence: 99%

Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

et al. 2018

View full text Add to dashboard Cite

The location and/or type of variants in FLNB result in a spectrum of osteochondrodysplasias ranging from mild forms, like spondylocarpotarsal synostosis syndrome and Larsen syndrome, to severe perinatal lethal forms, such as atelosteogenesis I and III and Boomerang dysplasia. Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. We report clinical features of 10 additional patients from 7 families with spondylocarpotarsal synostosis syndrome due to 7 novel deleterious variants in FLNB, thus expanding the clinical and molecular repertoire of spondylocarpotarsal synostosis syndrome. Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition.

show abstract

“…Six of these are immunoglobulin genes, suggesting ethanol effects on bone marrow cells. The strongest downregulation by ethanol (5.2-fold, P = 0.002) was for the gene for Myosin heavy chain 3 (Myh3), of which certain mutations can cause skeletal abnormalities (Carapito et al, 2016). Another gene known to have direct bone effects is Frzb encoding Frizzled Related Protein (Enomoto-Iwamoto et al, 2002).…”

Section: Chronic Alcohol Consumption Reduces Gene Expression Of Majormentioning

confidence: 99%

Chronic Ethanol Feeding in Mice Decreases Expression of Genes for Major Structural Bone Proteins in a Nox4-Independent Manner

Pedersen

Osborn

Robertson

et al. 2020

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Bone loss in response to alcohol intake has previously been hypothesized to be mediated by excessive production of reactive oxygen species (ROS) via NADPH oxidase (Nox) enzymes. Nox4 is one of several Nox enzymes expressed in bone. We investigated the role of Nox4 in the chondro-osteoblastic lineage of the long bones in mice during normal chow feeding and during chronic ethanol feeding for 90 days. We generated mice with a genotype (PrxCre +/-Nox4 fl/fl) allowing conditional knockout of Nox4 in the limb bud mesenchyme. Adult mice had 95% knockdown of Nox4 expression in the femoral shafts. For mice on regular chow, only whole-body Nox4 knockout mice had clearly increased cortical thickness and bone mineral density in the tibiae. When chronically fed a liquid diet with and without ethanol, conditional Nox4 knockout mice had slightly reduced dimensions of the cortical and trabecular regions of the tibiae (P < 0.1). The ethanol diet caused a significant reduction in cortical bone area and cortical thickness relative to a control diet without ethanol (P < 0.05). The ethanol diet further reduced gene expression of Frzb, Myh3 and several genes encoding collagen and other major structural bone proteins (P < 0.05), while the Nox4 genotype had no effects on these genes. In conclusion, Nox4 expression from both mesenchymal and non-mesenchymal cell lineages appears to exert subtle effects on bone. However, chronic ethanol feeding reduces cortical bone mass and cortical gene expression of major structural bone proteins in a Nox4-independent manner. Significance statement Excessive alcohol intake contributes to osteopenia and osteoporosis, with oxidative stress caused by the activity of NADPH oxidases hypothesized to be a mediator. We tested the role of NADPH oxidase 4 (Nox4) in osteoblast precursors in the long bones of mice with a conditional Nox4 knockout model. We found that Nox4 exerted effects independently of alcohol intake and ethanol effects on bone were Nox4 independent.

show abstract

Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome

Cited by 24 publications

References 29 publications

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

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

Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

Chronic Ethanol Feeding in Mice Decreases Expression of Genes for Major Structural Bone Proteins in a Nox4-Independent Manner

Contact Info

Product

Resources

About