Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype

Am J Hum Genet. 2002 Sep;71(3):656-62. doi: 10.1086/342259. Epub 2002 Jun 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Adaptor Proteins, Signal Transducing
  • Female
  • Gene Expression Profiling
  • Haplotypes / genetics
  • Humans
  • Macromolecular Substances
  • Male
  • Membrane Glycoproteins*
  • Membrane Proteins
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Protein Subunits
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Immunologic / genetics*
  • Receptors, Immunologic / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Triggering Receptor Expressed on Myeloid Cells-1


  • Actins
  • Adaptor Proteins, Signal Transducing
  • Macromolecular Substances
  • Membrane Glycoproteins
  • Membrane Proteins
  • Protein Subunits
  • RNA, Messenger
  • Receptors, Immunologic
  • TREM1 protein, human
  • TREM2 protein, human
  • TYROBP protein, human
  • Triggering Receptor Expressed on Myeloid Cells-1

Associated data

  • GENBANK/AA481924
  • GENBANK/BF343916
  • GENBANK/X00351
  • OMIM/221770