Expression of NOTCH2NL genes

Stable Identifier
R-HSA-9911233
DOI
10.3180/R-HSA-9911233.1
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Expression of NOTCH2NL genes
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The NOTCH2NL gene family includes four genes, NOTCH2NLA, NOTCH2NLB, NOTCH2NLC, and NOTCH2NLR, which originated from the partial duplication of the first four exons and introns of the NOTCH2 gene. Three of the duplicated genes, NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC, reside at the chromosomal band 1q21.1, while NOTCH2NLR resides at 1p12, in the vicinity of NOTCH2. NOTCH2NLA was originally cloned as a gene highly expressed in white blood cells (Duan et al. 2004). Several studies suggest that ,NOTCH2NL genes may have played a role in the evolutionary expansion of the human brain (Florio et al. 2018, Fiddes et al. 2018, Suzuki et al. 2018, Lodewijk et al. 2020). NOTCH2NL genes are present only in the Hominidae family and, while they are functional in humans, they exist as pseudogenes in chimpanzees and gorillas. In addition, these genes are highly expressed during brain development (Florio et al. 2018) and have the ability to delay differentiation of neuronal progenitors (Fiddes et al. 2018, Suzuki et al. 2018). The study of sequence polymorphism and copy number variation in NOTCH2NL genes in modern humans (Fiddes et al. 2018, Lodewijk et al. 2020), and comparative analysis of NOTCH2NL gene sequences between modern humans, Denisovans and Neanderthals (Lodewijk et al. 2020), is suggestive of an ongoing adaptive evolution of modern human NOTCH2NL genes trending toward lower levels of NOTCH2NL proteins. Downstream of each of the NOTCH2NL genes is an NBPF gene in the same orientation as its NOTCH2NL partner and co-expressed with it (NBPF10 downstream of NOTCH2NLA, NBPF14 downstream of NOTCH2NLB, NBPF19 downstream of NOTCH2NLC, and NBPF26 downstream of NOTCH2NLR), and these NOTCH2NL-NBPF pairs likely function in a coordinated, complementary fashion to promote neurogenesis and human brain expansion (Fiddes et al. 2019).

The neurodevelopmental disorder known as 1q21.1 distal deletion/duplication syndrome involves copy number gain or loss of the 1q21.1 chromosomal region that includes NOTCH2NLA and NOTCH2NLB genes. Copy number loss is associated with microcephaly, while copy number gain is associated with macrocephaly (Fiddes et al. 2018), and both gain and loss are accompanied with severe neurological disorders (Fiddes et al. 2018, Lodewijk et al. 2020). Breakpoints within NOTCH2NL gene loci are also associated with neurological disorders (Lodewijk et al. 2020).

Expansion of the GGC repeat in the 5’UTR of the NOTCH2NLC gene was identified as an important contributor to neuronal intranuclear inclusion disease (NIID) and may play a role in other neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), to name a few. The underlying pathogenic mechanism has not been elucidated. For review of NOTCH2NLC-related trinucleotide expansion disorders, please refer to Cao et al. 2021 and Huang et al. 2021.

Literature References
PubMed ID Title Journal Year
34333668 NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders

Cao, L, Yan, Y, Zhao, G

Neurol Sci 2021
34718964 The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review

Huang, XR, Tang, BS, Jin, P, Guo, JF

Mol Neurobiol 2022
29561261 Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex

Florio, M, Heide, M, Pinson, A, Brandl, H, Albert, M, Winkler, S, Wimberger, P, Huttner, WB, Hiller, M

Elife 2018
29856954 Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis

Fiddes, IT, Lodewijk, GA, Mooring, M, Bosworth, CM, Ewing, AD, Mantalas, GL, Novak, AM, van den Bout, A, Bishara, A, Rosenkrantz, JL, Lorig-Roach, R, Field, AR, Haeussler, M, Russo, L, Bhaduri, A, Nowakowski, TJ, Pollen, AA, Dougherty, ML, Nuttle, X, Addor, MC, Zwolinski, S, Katzman, S, Kriegstein, A, Eichler, EE, Salama, SR, Jacobs, FMJ, Haussler, D

Cell 2018
14673143 A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia

Duan, Z, Li, FQ, Wechsler, J, Meade-White, K, Williams, K, Benson, KF, Horwitz, M

Mol Cell Biol 2004
29856955 Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation

Suzuki, IK, Gacquer, D, Van Heurck, R, Kumar, D, Wojno, M, Bilheu, A, Herpoel, A, Lambert, N, Cheron, J, Polleux, F, Detours, V, Vanderhaeghen, P

Cell 2018
31087184 Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution

Fiddes, IT, Pollen, AA, Davis, JM, Sikela, JM

Hum Genet 2019
32330268 Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels

Lodewijk, GA, Fernandes, DP, Vretzakis, I, Savage, JE, Jacobs, FMJ

Mol Biol Evol 2020
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Authored
Orlic-Milacic, M  (2024-06-05)
Reviewed
Heide, M  (2024-10-26)
Created
Orlic-Milacic, M  (2024-05-27)
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