HGNC Approved Gene Symbol: LRRTM3
Cytogenetic location: 10q21.3 Genomic coordinates (GRCh38): 10:66,926,036-67,101,551 (from NCBI)
By database analysis using the leucine-rich repeats (LRRs) of the SLIT (see SLIT1; 603742) proteins, followed by RT-PCR of brain RNA, Lauren et al. (2003) cloned LRRTM3. The deduced 513-amino acid protein contains an N-terminal signal sequence, followed by 10 extracellular LRRs flanked by cysteine-rich domains, a transmembrane region, and an intracellular tail. LRRTM3 has 3 N-glycosylation sites, several putative phosphorylation sites, and a C terminus that ends in the sequence ECEV, which is a characteristic of LRRTM family members. Lauren et al. (2003) also identified mouse Lrrtm3, which shares 97% identity with human LRRTM3. RT-PCR analysis of human tissues detected LRRTM3 expression restricted to whole brain, including amygdala, caudate nucleus, cerebellum, corpus callosum, hippocampus, and thalamus. In developing mice, Lrrtm3 was expressed at embryonic day 13 and 15, reaching highest levels at postnatal day 1 that persisted into adulthood. In situ hybridization of adult mouse brain detected widespread Lrrtm3 expression predominantly in neurons.
The LRRTM3 gene maps to a region of chromosome 10q21 linked to both late-onset Alzheimer disease (AD6; 605526) and elevated plasma levels of pathogenic beta-amyloid (see APP; 104760). Using high-throughput small-interfering RNA (siRNA) screening of human embryonic kidney cells stably expressing APP, Majercak et al. (2006) found LRRTM3 promoted APP processing by BACE1 (604252). Knockdown of LRRTM3 with siRNAs inhibited the secretion of several beta-amyloid peptides and the N-terminal APP fragment produced by BACE1 from cultured cells and primary mouse neurons, whereas overexpression of LRRTM3 increased beta-amyloid secretion.
Lauren et al. (2003) determined that the LRRTM3 gene contains 2 coding exons.
By genomic sequence analysis, Lauren et al. (2003) mapped the LRRTM3 gene to chromosome 10q21.3, where it lies on the opposite strand within the largest 400-kb intron of the CTNNA3 gene (607667). They mapped the mouse Lrrtm3 gene to chromosome 10B4, which shares homology of synteny with human chromosome 10q21.3.
Lauren, J., Airaksinen, M. S., Saarma, M., Timmusk, T. A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics 81: 411-421, 2003. [PubMed: 12676565] [Full Text: https://doi.org/10.1016/s0888-7543(03)00030-2]
Majercak, J., Ray, W. J., Espeseth, A., Simon, A., Shi, X.-P., Wolffe, C., Getty, K., Marine, S., Stec, E., Ferrer, M., Strulovici, B., Bartz, S., and 17 others. LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease. Proc. Nat. Acad. Sci. 103: 17967-17972, 2006. [PubMed: 17098871] [Full Text: https://doi.org/10.1073/pnas.0605461103]