# ARMH1

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.

### 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 Isoform | Protein Accession | Protein Length | Molecular Weight | mRNA Isoform | mRNA Accession | mRNA length |
| X1 | XP_047275293 | 446 aa | 49.58 Kda | X5 | XM_011541340 | 1693 bp |
| X2 | XP_011539647 | 433 aa | 48.17 Kda | X7 | XM_011541345 | 1909 bp |
| X3 | XP_047275308 | 431 aa | 47.39 Kda | X8 | XM_047419352 | 1782 bp |
| X4 | XP_047275309 | 419 aa | 46.17 Kda | X9 | XM_047419353 | 1507 bp |
| X5 | XP_047275314 | 405 aa | 44.49 Kda | X12 | XM_047419358 | 1588 bp |
| X6 | XP_016856631 | 391 aa | 43.58 Kda | X13 | XM_017001142 | 1546 bp |
| X7 | XP_047275318 | 379 aa | 41.32 Kda | X14 | XM_047419362 | 1393 bp |
| X8 | XP_011539651 | 376 aa | 41.67 Kda | X15 | XM_011541349 | 1645 bp |
| X9 | XP_016856632 | 365 aa | 40.47 Kda | X16 | XM_017001143 | 1468 bp |
| X10 | XP_047275323 | 364 aa | 40.17 Kda | X17 | XM_047419367 | 1342 bp |
| X11 | XP_054192270 | 338 aa | 37.06 Kda | X18 | XM_054336295 | 1264 bp |
| X12 | XP_054192271 | 336 aa | 36.46 Kda | X19 | XM_054336296 | 1207 bp |
| X13 | XP_054192272 | 333 aa | 36.84 Kda | X20 | XM_054336297 | 1474 bp |
| x14 | XP_047275327 | 332 aa | 36.65 Kda | X21 | XM_047419371 | 1262 bp |
| x15 | XP_054192274 | 274 aa | 30.61 Kda | X23 | XM_054336299 | 1670 bp |
| x16 | XP_016856635 | 263 aa | 29.31 Kda | X24 | XM_017001146 | 1146 bp |
| x17 | XP_054192276 | 242 aa | 27.05 Kda | X25 | XM_054336301 | 2306 bp |
| x18 | XP_054192277 | 213 aa | 23.69 Kda | X26 | XM_054336302 | 1380 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. 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.