what is limb-girdle muscular dystrophy type 2I/R9?
Limb‑girdle muscular dystrophy type 2I/R9 (LGMD2I/R9) is a rare genetic disorder caused by variants in the fukutin‑related protein (FKRP ) gene. People living with LGMD2I/R9 experience progressive muscle degeneration and damage, and eventual loss of functional independence. BridgeBio, in partnership with the affiliate ML Bio Solutions, is committed to addressing the unmet needs of those affected by LGMD2I/R9 through the development of a novel oral therapy.
OUR RESEARCH
LGMD2I/R9
LGMD2I/R9 is a rare, recessive genetic disorder caused by variants in the FKRP gene. This gene encodes FKRP, an enzyme involved in a chemical process called glycosylation, during which sugar molecules are attached to proteins. This chain of sugars, known as a glycan chain, allows a critical stabilizer of the muscle cell membrane, alpha‑dystroglycan, to function correctly. In people with LGMD2I/R9, FKRP does not function at full capacity, leading to instability and injury of muscle cells. Physical symptoms of LGMD2I/R9 typically include loss of muscle mass and muscle wasting, leading to muscle weakness in the legs, arms, and trunk. At later stages, respiratory and cardiac muscles may also grow weak, which can cause respiratory and cardiac complications. Genetic testing is the only way to confirm a diagnosis of LGMD2I/R9.
glycosylated alpha‑dystroglycan
The major substrate of FKRP is alpha‑dystroglycan (αDG), which plays a critical role in stabilizing muscle cells. αDG is an essential component of the “shock absorption” system that exists to provide muscle cells with structural integrity. This system buffers muscle contractions and prevents scar tissue from forming during normal muscle use, such as during the beating of a heart, the expansion and contraction of the chest while breathing, and the movement of arm and leg muscles while walking.
LGMD2I/R9
LGMD2I/R9 is a rare, recessive genetic disorder caused by variants in the FKRP gene. This gene encodes FKRP, an enzyme involved in a chemical process called glycosylation, during which sugar molecules are attached to proteins. This chain of sugars, known as a glycan chain, allows a critical stabilizer of the muscle cell membrane, alpha‑dystroglycan, to function correctly. In people with LGMD2I/R9, FKRP does not function at full capacity, leading to instability and injury of muscle cells. Physical symptoms of LGMD2I/R9 typically include loss of muscle mass and muscle wasting, leading to muscle weakness in the legs, arms, and trunk. At later stages, respiratory and cardiac muscles may also grow weak, which can cause respiratory and cardiac complications. Genetic testing is the only way to confirm a diagnosis of LGMD2I/R9.
glycosylated alpha‑dystroglycan
The major substrate of FKRP is alpha‑dystroglycan (αDG), which plays a critical role in stabilizing muscle cells. αDG is an essential component of the “shock absorption” system that exists to provide muscle cells with structural integrity. This system buffers muscle contractions and prevents scar tissue from forming during normal muscle use, such as during the beating of a heart, the expansion and contraction of the chest while breathing, and the movement of arm and leg muscles while walking.
Healthy muscle tissue
LGMD2I/R9 muscle tissue
αDG, alpha‑dystroglycan; CDP, cytidine diphosphate; CTP, cytidine triphosphate; FKRP, fukutin‑related protein; ISPD, isoprenoid synthase domain‑containing protein; LGMD2I/R9, limb‑girdle muscular dystrophy type 2I/R9; P, phosphate; R, ribitol.
To function, αDG requires glycosylation by FKRP, which adds sugars to αDG in an assembly line‑like fashion. In people with LGMD2I/R9, FKRP does not function at full capacity, and αDG does not become fully glycosylated. As a result, the shock absorber function is lost, causing muscles to become damaged with use and eventually form scar‑like, fibrotic tissue. As the proportion of fibrotic tissue within the muscle increases, there is a decline in muscle strength and function. Loss of muscle strength eventually causes people affected by LGMD2I/R9 to lose the ability to perform routine daily activities, such as walking or standing up, without assistance.
