- Please check and comment entries here.
Atelosteogenesis Type 3
Atelosteogenesis type 3 is a disorder that affects the development of bones throughout the body. Affected individuals are born with inward- and upward-turning feet (clubfeet) and dislocations of the hips, knees, and elbows. Bones in the spine, rib cage, pelvis, and limbs may be underdeveloped or in some cases absent. As a result of the limb bone abnormalities, individuals with this condition have very short arms and legs. Their hands and feet are wide, with broad fingers and toes that may be permanently bent (camptodactyly) or fused together (syndactyly). Characteristic facial features include a broad forehead, wide-set eyes (hypertelorism), and an underdeveloped nose. About half of affected individuals have an opening in the roof of the mouth (a cleft palate.)
Individuals with atelosteogenesis type 3 typically have an underdeveloped rib cage that affects the development and functioning of the lungs. As a result, affected individuals are usually stillborn or die shortly after birth from respiratory failure. Some affected individuals survive longer, usually with intensive medical support. They typically experience further respiratory problems as a result of weakness of the airways that can lead to partial closing, short pauses in breathing (apnea), or frequent infections. People with atelosteogenesis type 3 who survive past the newborn period may have learning disabilities and delayed language skills, which are probably caused by low levels of oxygen in the brain due to respiratory problems. As a result of their orthopedic abnormalities, they also have delayed development of motor skills such as standing and walking.
Atelosteogenesis type 3 is a rare disorder; its exact prevalence is unknown. About two dozen affected individuals have been identified.
Mutations in the FLNB gene cause atelosteogenesis type 3. The FLNB gene provides instructions for making a protein called filamin B. This protein helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Filamin B attaches (binds) to another protein called actin and helps the actin to form the branching network of filaments that makes up the cytoskeleton. It also links actin to many other proteins to perform various functions within the cell, including the cell signaling that helps determine how the cytoskeleton will change as tissues grow and take shape during development.
Filamin B is especially important in the development of the skeleton before birth. It is active (expressed) in the cell membranes of cartilage-forming cells (chondrocytes). Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone (a process called ossification), except for the cartilage that continues to cover and protect the ends of bones and is present in the nose, airways (trachea and bronchi), and external ears. Filamin B appears to be important for normal cell growth and division (proliferation) and maturation (differentiation) of chondrocytes and for the ossification of cartilage.
FLNB gene mutations that cause atelosteogenesis type 3 change single protein building blocks (amino acids) in the filamin B protein or delete a small section of the protein sequence, resulting in an abnormal protein. This abnormal protein appears to have a new, atypical function that interferes with the proliferation or differentiation of chondrocytes, impairing ossification and leading to the signs and symptoms of atelosteogenesis type 3.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family.
5. Other Names for This Condition
- atelosteogenesis type III
This entry is adapted from https://medlineplus.gov/genetics/condition/atelosteogenesis-type-3
- Farrington-Rock C, Firestein MH, Bicknell LS, Superti-Furga A, Bacino CA,Cormier-Daire V, Le Merrer M, Baumann C, Roume J, Rump P, Verheij JB, Sweeney E, Rimoin DL, Lachman RS, Robertson SP, Cohn DH, Krakow D. Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat. 2006 Jul;27(7):705-10.
- Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C,Wachsmann-Hogiu S, Acuna D, Shapiro SS, Takafuta T, Aftimos S, Kim CA, Firth H,Steiner CE, Cormier-Daire V, Superti-Furga A, Bonafe L, Graham JM Jr, Grix A,Bacino CA, Allanson J, Bialer MG, Lachman RS, Rimoin DL, Cohn DH. Mutations inthe gene encoding filamin B disrupt vertebral segmentation, joint formation andskeletogenesis. Nat Genet. 2004 Apr;36(4):405-10.
- Sawyer GM, Clark AR, Robertson SP, Sutherland-Smith AJ. Disease-associatedsubstitutions in the filamin B actin binding domain confer enhanced actin bindingaffinity in the absence of major structural disturbance: Insights from thecrystal structures of filamin B actin binding domains. J Mol Biol. 2009 Jul31;390(5):1030-47. doi: 10.1016/j.jmb.2009.06.009.
- Schultz C, Langer LO, Laxova R, Pauli RM. Atelosteogenesis type III: long termsurvival, prenatal diagnosis, and evidence for dominant transmission. Am J MedGenet. 1999 Mar 5;83(1):28-42.