Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.
The distal arthrogryposes (DAs) are a group of disorders characterized by multiple congenital contractures of the limbs. We previously mapped a locus for DA type 2B (DA2B), the most common of the DAs, to chromosome 11. We now report that DA2B is caused by mutations in TNNI2 that are predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI) specific to the troponin-tropomyosin (Tc-Tm) complex of fast-twitch myofibers. Because the DAs are genetically heterogeneous, we sought additional candidate genes by examining modifiers of mutant Drosophila isoforms of TnI. One of these modifiers, Tm2, encodes tropomyosin, another component of the Tc-Tm complex. A human homologue of Tm2, TPM2, encodes beta-tropomyosin and maps to the critical interval of DA type 1 (DA1). We discovered that DA1 is caused by substitution of a highly conserved amino acid residue in beta-tropomyosin. These findings suggest that DAs, in general, may be caused by mutations in genes encoding proteins of the contractile apparatus specific to fast-twitch myofibers. This provides a new opportunity to directly study the etiology and pathogenesis of multiple-congenital-contracture syndromes.
Sung
Sandy S
SS
Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
Brassington
Anna-Marie E
AM
Grannatt
Kathryn
K
Rutherford
Ann
A
Whitby
Frank G
FG
Krakowiak
Patrycja A
PA
Jorde
Lynn B
LB
Carey
John C
JC
Bamshad
Mike
M
D000595:Amino Acid Sequence; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D012189:Retrospective Studies; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014335:Tropomyosin / Q000235:genetics; D014336:Troponin / Q000737:chemistry / Q000235:genetics*
D009124:Muscle Proteins; D014335:Tropomyosin; D014336:Troponin