This report describes distal arthrogryposis, type 1, MYH3-related; DA1 is a less severe subtype of DA and typically exhibits autosomal dominant inheritance. OMIM does not include a DA1 subtype associated with MYH3, but describes the specific F437I variant of MYH3 as potentially associated with DA1(see MIM:618436).
The human gene implicated in this disease, MYH3, is one of ten muscle myosin class II heavy chain genes in human. MYH3 is described as embryonic skeletal muscle myosin heavy chain, and forms part of a myosin protein complex that is normally active only before birth and is important for early development of the muscles. In flies there is one gene, Mhc, orthologous to the ten genes in humans that encode forms of muscle myosin class II heavy chain. (The fly gene zip is orthologous to the non-muscle myosin class II heavy chain genes.) MYH3 is implicated in other forms of arthrogryposis (DA2A and DA2B3); these diseases also exhibit autosomal dominant inheritance.
A UAS construct of a wild-type tagged human Hsap\MYH3 gene has been introduced into flies, but has not been characterized.
Classical amorphic and hypomorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for the Mhc gene. Phenotypes of amorphic alleles of Mhc range from lethality to flight defective; defects in myofibrils and sarcomeres are observed. Extensive genetic and physical interactions of Dmel\Mhc have been described; see below and in the Mhc gene report.
Mutations analogous to variants implicated in DA1 in the human MYH3 gene have been generated in Dmel\Mhc. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): F435I in the fly Mhc gene (corresponds to F437I in the human MYH3 gene); A232T in the fly Mhc gene (corresponds to A234T in the human MYH3 gene. The A234T variant has also been implicated in a more severe form of distal arthrogryposis (see FBhh0001267). As in humans, the disease-implicated variants display dominant defects in muscle function: myofibrillar morphology and stability are perturbed; reductions in myosin ATPase activity and reduced power output are observed.
[updated Oct. 2020 by FlyBase; FBrf0222196]
The distal arthrogryposes are a group of disorders characterized by contractures mainly involving the distal parts of the limbs. The hands have a characteristic position with medially overlapping fingers, clenched fists, ulnar deviation of fingers, and camptodactyly, and the feet have deformities. Contractures at other joints are variable; there are no associated visceral anomalies, and intelligence is normal. The various phenotypic forms of distal arthrogryposis are classified hierarchically according to the proportion of features they share with one another and are designated DA1 through DA10 (summary by Bamshad et al. 2009; pubmed:19571066). [from MIM:108120; 2020.10.17]
The prototypic distal arthrogryposis is type 1 (DA1), which is characterized largely by camptodactyly and clubfoot. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. [from MIM:108120; 2020.10.17]
Intrafamilial variable expression of DA1 and DA2B in related individuals harboring A234T has been reported (Kimber et al., 2012; pubmed:22519952). [from ClinVar, variation 141450; 2020.10.17]
Many to one: 10 human genes to 1 Drosophila gene.
Ortholog of human muscle myosin heavy chain genes, class II (1 Drosophila to 10 human); Dmel\Mhc shares 56% identity and 74% similarity with the human MYH3 gene.
