OSTM1

OSTM1 stands for osteopetrosis-associated transmembrane protein 1, a gene that encodes a lysosomal membrane protein essential for osteoclast function. In humans, OSTM1 forms a stable functional complex with CLCN7 to enable proper lysosomal acidification by providing chloride conductance required during bone resorption. The protein localizes primarily to lysosomes and endosomes and is thought to stabilize CLCN7 and promote its trafficking to the lysosome.

Genetics and expression: OSTM1 is expressed in osteoclasts and other tissues, reflecting a broader role in lysosomal biology. Mutations in OSTM1 cause autosomal recessive osteopetrosis, often described as infantile malignant osteopetrosis, characterized by defective bone resorption and dense skeletal bones. Associated features can include hepatosplenomegaly, anemia, and cranial nerve compression; some patients also exhibit neurodegenerative features due to lysosomal dysfunction in neurons, expanding the clinical spectrum.

Function and mechanism: The OSTM1–CLCN7 complex is required for the electroneutral chloride/proton exchange that neutralizes charge as protons are pumped into the resorption lacuna by V-ATPase. Loss of OSTM1 disrupts lysosomal pH homeostasis, osteoclast maturation, and lysosome function, leading to impaired bone remodeling and accumulation of dense bone tissue.

Clinical implications: Diagnosis relies on a combination of clinical features, radiographs, and genetic testing for OSTM1 mutations. Treatments are primarily supportive; hematopoietic stem cell transplantation can be curative in some forms of autosomal recessive osteopetrosis caused by osteoclast dysfunction, though outcomes vary with early intervention. Research continues into the precise molecular roles of OSTM1 in neurons and other lysosome-related processes.