Armadillo-like Helical Domain Containing 1 (ARMH1) is a protein which in humans is encoded by chromosome 1 open reading frame 228, also known as the ARMH1 gene. The gene shows expression levels significantly higher in bone marrow, lymph nodes, and testis. Currently the function of this gene and subsequent protein is still uncertain.
Gene The ARMH1 gene is found on the plus strand of chromosome 1 between base pairs 45,140,361 and 45,191,784. Other known aliases include P40, NCRNA00082, and most commonly C1orf228. The gene has 13 exons, most of which are concentrated near the poly-A site at the end of the gene and two located upstream from the start codon. The gene is highly expressed in bone marrow and lymph nodes, suggesting an immunological function.https://www.genecards.org/cgi-bin/carddisp.pl?gene=ARMH1>
Gene expression RNA seq data was produced using multiple samples of human tissues at varying stages of development. One study was acquired from 20 separate samples of human tissue showing significantly more expression of ARMH1 in the thymus, trachea, and lungs. A second study shows 27 different tissues samples in 95 different individual subjects. The expression levels are significantly higher in bone marrow, lymph nodes, and testis. A third shows high expression in white blood cells and testis again, corroborating previous studies. A temporal study focused on expression in different stages of development collected 35 human fetal samples, from 6 distinct tissues, between 10 and 20 weeks gestational time and sequenced using Illumina TruSeq Stranded Total RNA. The data slightly favored expression in the adrenal glands throughout development. In each of the other tissues there were no stark changes in expression through time, only a small decline of gene expression as development furthers.
Gene transcripts The ARMH1 gene has extensive abilities to alter its function and size through isoforms. Gene isoforms are mRNAs that are produced from the same locus but are different in their transcription start sites, protein coding DNA sequences and/or untranslated regions, potentially altering gene function. All known isoforms are organized and listed below with information gathered from NCBI gene, and a Bioinformatics tool for calculating molecular weight. Protein IsoformProtein AccessionProtein LengthMolecular WeightmRNA IsoformmRNA Accession mRNA lengthX1XP_047275293446 aa49.58 KdaX5XM_0115413401693 bpX2XP_011539647433 aa48.17 KdaX7XM_0115413451909 bpX3XP_047275308431 aa47.39 KdaX8XM_0474193521782 bpX4XP_047275309419 aa46.17 KdaX9XM_0474193531507 bpX5XP_047275314405 aa44.49 KdaX12XM_0474193581588 bpX6XP_016856631391 aa43.58 KdaX13XM_0170011421546 bpX7XP_047275318379 aa41.32 KdaX14XM_0474193621393 bpX8XP_011539651376 aa41.67 KdaX15XM_0115413491645 bpX9XP_016856632365 aa40.47 KdaX16XM_0170011431468 bpX10XP_047275323364 aa40.17 KdaX17XM_0474193671342 bpX11XP_054192270338 aa37.06 KdaX18XM_0543362951264 bpX12XP_054192271336 aa36.46 KdaX19XM_0543362961207 bpX13 XP_054192272333 aa36.84 KdaX20XM_0543362971474 bpx14XP_047275327332 aa36.65 KdaX21XM_0474193711262 bpx15XP_054192274274 aa30.61 KdaX23XM_0543362991670 bpx16XP_016856635263 aa29.31 KdaX24XM_0170011461146 bpx17XP_054192276242 aa27.05 KdaX25XM_0543363012306 bpx18XP_054192277213 aa23.69 KdaX26XM_0543363021380 bp
mRNA The mRNA for this gene can be spliced in many different ways, making way for approximately 20 known isoforms. The most common mRNA gets spliced down to a coding region that is about 1693 nucleotides long which makes up 440 amino acids in total.> nih.gov In a comprehensive study on oral squamous cell carcinoma, the sixth most prevalent cancer worldwide, identified ARMH1 as a gene of interest by comparing healthy subjects mRNA against affected individuals. Through mRNA inhibition of ARMH1, researchers demonstrated significantly reduced leukemic cell proliferation (P=.0041) and leukemic cell migration (P=.0001), as well as a decreased resistance to the chemotherapy drug Cytarabine.
Protein The protein encoded by the gene goes by the same name, Armadillo like containing helical domain 1. The isoelectric point of the ARMH1 protein is around a pH of 5.5. The protein has 2 known major domains, one being a transmembrane domain and the other being a coiled coil. Within the coiled coil domains, the ARMH1 protein has 24 alpha helices. The European Bioinformatics Institute's analysis of ARMH1 reveals clearly a significantly enriched lysine content as well as a significantly deficient proline count. The protein has been proven to have one major interaction with the human protein known as ABAT. Gamma-aminobutyric acid transaminase (ABAT) catalyzes the conversion of gamma-aminobutyric acid (GABA) into succinic semialdehyde. Additionally, ABAT expression was associated with glycolysis-related genes, infiltrated immune cells, immunoinhibitors, and immunostimulators in HCC.
Homology and evolution The ARMH1 gene is extremely diverse and is found in thousands of different species. From primates to fungus, this gene has been evolutionarily relevant for hundreds of millions of years. While in near relatives such as cows, the similarity score is 91% that of our genome, in species of fungi the similarity ranges between 20 and 30%. While attempting to find homologs in any round or flat worms, single celled eukaryotes or prokaryotes, plants, or any fungi besides chitrids, there were no significantly similar genes found. Below is a table of orthologous genes in order of sequence similarity compared to the human ARMH1 isoform X1. Species Common name Accession number Date of divergence Sequence length (AA) Sequence similarity Sequence identity Homo sapiens Human NP_001139108 0 mya 440 100% 100% Microcebus murinus Grey Mouse Lemur XP_012631405.1 74 mya 441 88% 82% Rattus norvegicus Brown Rat NP_001119769.2 87 mya 441 80% 78% Bos taurus Cow XP_005204913.1 94 mya 442 91% 83% Ornithorhynchus anatinus Platypus XP_028938784.1 180 mya 459 75% 60% Apteryx rowi Oktarito Kiwi XP_025942684 319 mya 419 73% 59% Haliaeetus leucocephalus Bald Eagle XP_010581029 319 mya 418 70% 56% Gopherus flavomarginatus Bolson Tortoise XP_050817160 319 mya 421 78% 65% Xenopus tropicalis Western Clawed Frog XP_017949069 352 mya 409 70% 55% Danio rerio Zebra Fish XP_001341083.1 429 mya 410 71% 53% Leucoraja erinacea Little Skate XP_055497706 462 mya 406 69% 53% Lytechinus pictus Painted Urchin XP_054764007 619 mya 406 67% 51% Owenia fusiformis Segmented Worm CAH1776102.1 686 mya 410 71% 51% Aplysia californica California Sea Hare XP_012936639.1 708 mya 410 69% 52% Adineta sterineri Rotifera CAF4083605.1 708 mya 420 56% 37% Pocillopora verrucosa Colonial Coral XP_058955966.1 708 mya 404 67% 49% Geodia barretti Sea Sponge CAI8036895.1 758 mya 404 50% 35% Blastocladiella britannica Chytrids KAI9218662 1275 mya 423 34% 22% Borealophlyctis nickersoniae Rhizophlyctidales KAJ3289137 1275 mya 453 19% 11%
Clinical significance The ARMH1 gene and subsequent protein have been extensively linked to leukemia, specifically T-cell acute lymphoblastic leukemia (T-ALL). In mostly lymphatic tissue cell lines, T-ALL showed dramatically increased expression of the ARMH1 gene. Bone marrow samples were taken at the initial diagnosis and the conclusion of treatment and ARMH1 along with 5 other genes that were all found to be dramatically changed in expression. Researchers Dr. Manoj Bhasin and Dr. Mojtaba Bakhtiari from Emory University's Aflac Cancer Center have identified ARMH1, a novel cancer-associated gene, as being highly expressed in malignant blast cells across several pediatric hematologic malignancies, including AML, T/B-ALL, and T/B-MPAL. Importantly, ARMH1 expression is significantly elevated in patients with relapsed disease or high-risk cytogenetic profiles (e.g., MLL rearrangements) compared to those with standard-risk markers (e.g., RUNX1, inv(16)). Additionally, ARMH1 expression strongly correlates with the pediatric leukemia stem cell score (LSC6), a six-gene signature linked to poor prognosis.
Functional studies involving ARMH1 perturbation (via knockdown and overexpression) in leukemia cell lines revealed substantial effects on cell proliferation and migration. RNA sequencing of these modified cells highlighted associations between ARMH1 and pathways related to mitochondrial fatty acid synthesis and the cell cycle. Pharmacological inhibition of CPT1A, a key regulator of fatty acid synthesis in the mitochondrial matrix, led to ARMH1 downregulation, along with reduced CPT1A levels, ATP production, and oxygen consumption rates. Furthermore, ARMH1 knockdown caused a notable decrease in cell cycle regulators, including CDCA7 and EZH2.
The research also uncovered that ARMH1 physically interacts with EZH2, a protein implicated in multiple cancers, suggesting its critical role in oncogenesis. These findings establish ARMH1 as a key player in mitochondrial metabolism and cell cycle regulation, positioning it as a potential target for therapeutic intervention in pediatric hematologic malignancies.
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