Molecular Characteristics

FIG4 encodes a lipid phosphatase that regulates vesicles transportation inside cells. It is part of a complex that regulates the signaling phosphoinositides PI(3,5)P2. The production of PI(3,5)P2 at the cytoplasmic surface of intracellular vesicles interacts with effector proteins to regulate endosomal vesicle fusion and trafficking, and autophagy. Mutations in FIG4 lead to the instability of the complex, a diminution in PI(3,5)P2 concentration and an accumulation of enlarged intracellular vacuoles containing lysosomal membrane proteins LAMP1 and LAMP2. FIG4 is thought to be essential in postmigration development of neurons. FIG4 deficiency alters membranous and endochondral ossification, skeletal maintenance, and motor-neuron survival.

BTOP is inherited in an autosomal recessive manner. Variants result in partial loss of function.

CMT4J is inherited in an autosomal recessive manner. It is caused by compound heterozygosity for a null and a missense variants, resulting in partial loss of function.

ALS11 is inherited in an autosomal dominant manner. Five unrelated individuals were found with heterozygous missense, splice site or truncating variants .

YVS is inherited in an autosomal recessive manner. Twenty-five cases from nineteen families have been reported. Homozygous and compound heterozygous variants in FIG4 have been identified and resulted in complete loss of function. An imbalance in bone formation and resorption caused by defect of osteoblasts and osteoclasts is thought to underly this disease.