Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype

Abstract

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype.

Neuroinflammation: Ways in Which the Immune System Affects the Brain

“…Microglia progenitors enter the CNS at embryonic day 9.5-10.5 [1,2], prior to the emergence and differentiation of other nervous system glial-cell types, and consistent with their critical role in shaping CNS development. The role of microglia in brain development and function was suggested by investigation of Nasu-Hakola disease, a rare genetic dementing leukoencephalopathy caused by homozygous deficiency of triggering receptor on myeloid cells 2 (TREM2), which is only expressed in the CNS on microglia [15]. Moreover, using in vivo 2-photon imaging, the processes of cortical microglia can be shown to be constantly active, surveying the brain parenchyma every 4 h and interacting with synapses [16,17].…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…It is an innate immune receptor expressed on the extracellular membrane of activated macrophages, osteoclast, immature dendritic cells, and microglia in the brain (Takahashi et al 2005). Its signaling capacity is carried out through forming a complex with the TYRO protein tyrosine kinase binding protein (TYROBP, also known as DAP12) (Paloneva et al 2002). The TREM2/ TYROBP complex is reported to regulate key signaling pathways involved in differentiation of dendritic cells and osteoclasts, phagocytic activity in microglia and immune responses (Bouchon et al 2001;Hsieh et al 2009;Otero et al 2012).…”

Cutting Edge: Inhibition of TLR and FcR Responses in Macrophages by Triggering Receptor Expressed on Myeloid Cells (TREM)-2 and DAP12

“…In humans, mutation of either DAP12 or TREM-2 results in Nasu-Hakola syndrome, a rare disease characterized by bone cysts and presenile dementia (10,18). This phenotype implies a role for the TREM-2-DAP12 receptor complex in osteoclast and microglia differentiation and function.…”