TYROBP Gene: Function, Mutations, and Associated Diseases

TYROBP encodes the transmembrane adaptor protein DAP12 (also known as KARAP). DAP12 is a key signaling component of multiple immunoreceptors, including those on natural killer (NK) cells, myeloid cells, and osteoclasts. It contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Upon receptor engagement, DAP12 recruits SYK or ZAP70 kinases to initiate downstream signaling cascades. Mutations in TYROBP cause Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL), and variants are associated with increased risk for Alzheimer's disease and other neurodegenerative conditions.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Immunoreceptor signaling (NK cells

• myeloid cells)

• Osteoclast differentiation (RANKL signaling)

• Alzheimer's disease microglial activation

DAP12 (TYROBP) is a 113-amino-acid transmembrane adaptor protein with a short extracellular domain, a transmembrane domain containing a charged aspartic acid residue, and a cytoplasmic ITAM. It forms disulfide-linked homodimers and non-covalently associates with activating receptors such as NKG2C, KIR2DS, TREM2, and SIRPB1. Upon ligand binding, DAP12 ITAM tyrosines are phosphorylated by Src family kinases, recruiting SYK/ZAP70 to propagate signals. DAP12 is essential for NK cell cytotoxicity, cytokine production, osteoclast bone resorption, and microglial function.