ASH1L
ASH1L (also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) is a
Gene
Ash1 was discovered as a gene causing an imaginal disc mutant phenotype in Drosophila. Ash1 is a member of the
The human ASH1L gene spans 227.5 kb on chromosome 1, band q22. This region is rearranged in a variety of human cancers such as leukemia, non-Hodgkin’s lymphoma, and some solid tumors. The gene is expressed in multiple tissues, with highest levels in brain, kidney, and heart, as a 10.5-kb mRNA transcript.[7] Mutations in ASH1L in humans have been associated with autism, epilepsy, and intellectual disability.[8]
Structure
Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa.
The SET domain is responsible for ASH1L’s histone methyltransferase (HMTase) activity. Unlike other proteins that contain a SET domain at their C terminus, ASH1L has a SET domain in the middle of the protein. The crystal structure of the human ASH1L catalytic domain, including the AWS, SET, and post-SET domains, has been solved to 2.9 angstrom resolution. The structure shows that the substrate binding pocket is blocked by a loop from the post-SET domain, and because mutation of the loop stimulates ASH1L HMTase activity, it was proposed that this loop serves a regulatory role.[10]
Protein expression patterns and timing
ASH1L is ubiquitously expressed throughout the body.[11][12][13][14] In the brain, ASH1L is expressed across brain areas and cell types, including excitatory and inhibitory neurons, astrocytes, oligodendrocytes, and microglia.[15][16][17] ASH1L also does not appear to show specificity to any brain region. In humans, ASH1L mRNA expression levels are fairly equal across all regions of cortex.[18][19] Similarly, in mice, ASH1L protein is highly expressed in the hippocampus, thalamus, hypothalamus, motor cortex, and basolateral amygdala.[20] In humans, ASH1L expression peaks prenatally and decreases after birth, with a second peak in expression towards adulthood.[18][19] In mouse, ASH1L is expressed in the developing central nervous system as early as embryonic day 8.5 [21][13] and is still expressed throughout the adult mouse brain.[22] Overall, the expression of ASH1L in the brain is spatially and temporally broad.
Function
The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling.
A Hox promoter reporter construct in HeLa cells requires both
The in vivo target for ASH1L’s HMTase activity has been a topic of some controversy. Blobel’s group found that in vitro ASH1L methylates H3K4 peptides, and the distribution of ASH1L across transcribed genes resembles that of H3K4 levels.[23] In contrast, two other groups have found that ASH1L’s HMTase activity is directed toward H3K36, using nucleosomes as substrate.[10][24]
Role in human disease
There are over 100 reported pathogenic, or disease-causing, variants in the ASH1L gene.[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] About half of the variants arise de novo, and half are inherited. Of the inherited variants, about half are maternally inherited and half are paternally inherited. Disease-causing variants may be missense, nonsense, or frameshift mutations. The missense mutations are distributed throughout the gene body without localizing to a known functional domain of ASH1L.
All affected humans are heterozygous for ASH1L mutations. A single pathogenic copy of ASH1L causes disease, which may be the result of two different genetic mechanisms: haploinsufficiency or dominant negative function. The ClinGen clinical genomics resource states that there is “Sufficient Evidence for Haploinsufficiency” in ASH1L.[48]
The most common phenotypes, or symptoms, related to ASH1L mutations are autism spectrum disorder (ASD), epilepsy, intellectual disability, and attention deficit hyperactivity disorder (ADHD). The Simons Foundation Autism Research Initiative (SFARI) gives ASH1L a score of 1.1, indicating that ASH1L is a high confidence autism gene with the best level of evidence linking it to autism.[8]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000116539 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028053 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 22140534.
- PMID 10454589.
- ^ PMID 10860993.
- ^ a b "Gene: ASH1L -". Retrieved 2024-01-22.
- ^ "ASH1L_HUMAN". UniProt. Retrieved 24 August 2012.
- ^ PMID 21239497.
- ^ "ASH1L protein expression summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2024-02-15.
- PMID 25613900.
- ^ PMID 30335138.
- PMID 24309898.
- PMID 30382198.
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- ^ PMID 24695229.
- ^ PMID 35210569.
- PMID 27229316.
- PMID 30186101.
- S2CID 4421492.
- ^ PMID 17923682.
- PMID 17544230.
- PMID 29276005.
- PMID 25363760.
- PMID 26350204.
- S2CID 9243148.
- S2CID 21674196.
- S2CID 235691774.
- PMID 26325558.
- PMID 26785492.
- PMID 32469098.
- PMID 23033978.
- PMID 27824329.
- PMID 33004838.
- PMID 25363768.
- PMID 28191889.
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- PMID 30564305.
- PMID 35982159.
- PMID 28263302.
- PMID 25961944.
- PMID 34582790.
- PMID 34356069.
- PMID 31209962.
- ^ "ASH1L curation results". search.clinicalgenome.org. Retrieved 2024-01-22.
External links
- Human ASH1L genome location and ASH1L gene details page in the UCSC Genome Browser.
- Simons Foundation Autism Research Initiative gene page on ASH1L
- Clinical Genome Resource information on ASH1L
- CARE4ASH1L family foundation for families affected by mutations in ASH1L
Further reading
- Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O (February 2000). "Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (1): 65–73. PMID 10718198.
- Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, et al. (June 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–716. S2CID 27764390.
- Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–1332. PMID 15231748.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. PMID 16344560.
- Vasilescu J, Zweitzig DR, Denis NJ, Smith JC, Ethier M, Haines DS, Figeys D (January 2007). "The proteomic reactor facilitates the analysis of affinity-purified proteins by mass spectrometry: application for identifying ubiquitinated proteins in human cells". Journal of Proteome Research. 6 (1): 298–305. PMID 17203973.