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FB2026_01
,
released March 12, 2026
This report describes distal arthrogryposis, type 2A (DA2A); DA2A exhibits autosomal dominant inheritance. The human gene implicated in this disease is MYH3, 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 several other forms of arthrogryposis (DA2B and DA8); 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 specific to DA2A in the human MYH3 gene have been generated in Dmel\Mhc. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R672C in the fly Mhc gene (corresponds to R672C in the human MYH3 gene); R672H in the fly Mhc gene (corresponds to R672H in the human MYH3 gene); T178I in the fly Mhc gene (corresponds to T178I in the human MYH3 gene); Y582S in the fly Mhc gene (corresponds to Y583S in the human MYH3 gene). The mutated transgenes were characterized in a genetic background homozygous or heterozygous for a null mutation of the endogenous Mhc gene. As in humans, the disease-implicated variants display dominant defects in muscle function, with varying severity depending on the allele expressed; myofibrillar morphology and stability is perturbed; reductions in ATPase activity and actin sliding velocity are observed.
[updated Feb. 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]
[ARTHROGRYPOSIS, DISTAL, TYPE 2A; DA2A](https://omim.org/entry/193700)
[MYOSIN, HEAVY CHAIN 3, SKELETAL MUSCLE, EMBRYONIC; MYH3](https://omim.org/entry/160720)
In general, 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. In addition to contractures of the hands and feet, DA2A/FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, DA2A has been called 'whistling face syndrome.' [from MIM:108120, MIM:193700; 2019.03.12]
Mutations in this gene can also cause distal arthrogryposis type 2B (DA2B), also known as Sheldon-Hall syndrome, and distal arthrogryposis type 8 (DA8). [from MIM:193700; 2019.03.12]
Distal arthrogryposis type 2A (DA2A) is caused by heterozygous mutation in the MYH3 gene. [from MIM:193700; 2019.03.12]
Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. [Gene Cards, MYH3; 2019.03.12]
MYH3 encodes embryonic skeletal muscle myosin heavy chain 3, which forms part of a myosin protein complex that is normally active only before birth and is important for early development of the muscles. [Genetics Home Reference, MYH3; 2019.03.12]
Many to one: 10 human to 1 Drosophila.
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.