Histidine Change
Introduction
Section titled “Introduction”A histidine change refers to a specific type of missense mutation, a single nucleotide polymorphism (SNP) that results in the alteration of a histidine amino acid residue within a protein sequence. This can involve either the substitution of histidine for a different amino acid or the replacement of a histidine by another amino acid. Such changes are classified as non-synonymous polymorphisms because they lead to a modification in the protein’s primary structure.
Biological Basis
Section titled “Biological Basis”The biological significance of a histidine change stems from the unique properties of histidine. Its imidazole side chain has a pKa value close to physiological pH, allowing it to readily gain or lose a proton. This makes histidine critical for various protein functions, including enzyme catalysis, proton shuttling, and coordination of metal ions within proteins. An alteration involving histidine can therefore profoundly impact a protein’s three-dimensional structure, stability, and functional activity. For instance, if a histidine is located in an enzyme’s active site or a crucial binding interface, its modification could impair or abolish the protein’s biological role.
Clinical Relevance
Section titled “Clinical Relevance”Amino acid changes, including those involving histidine, can have significant clinical consequences by altering protein function, leading to a wide range of phenotypic variations or disease susceptibility. For example, a non-synonymous polymorphism (rs8176746 ) in the ABOgene results in a leucine to methionine amino acid change, which is fundamental in determining the B blood group.[1] Similarly, mutations in HK1are associated with severe nonspherocytic hemolytic anemia.[2] Other research highlights the clinical impact of missense mutations, such as those in the amyloid precursor proteingene linked to familial Alzheimer’s disease, or the Val58Ile polymorphism inchondromodulin-IIassociated with radiographic joint destruction in rheumatoid arthritis.[3]These examples underscore how changes to specific amino acids can disrupt normal biological processes and contribute to disease.
Social Importance
Section titled “Social Importance”Understanding histidine changes and other amino acid alterations holds considerable social importance in the era of genomic medicine. The identification of such functional variants through genome-wide association studies (GWAS) and other genetic analyses contributes to a deeper comprehension of complex traits and disease mechanisms.[4]This knowledge is crucial for advancements in personalized medicine, enabling more accurate disease risk assessment, guiding therapeutic strategies, and facilitating the development of targeted drug interventions. By elucidating how specific amino acid changes influence human health, researchers can pave the way for improved diagnostic tools and more effective treatments.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Initial genome-wide association studies (GWAS) often face challenges related to sample size and statistical power, which can limit the detection of genetic variants with small effect sizes and increase the likelihood of false negative findings for ‘histidine change’. While meta-analyses combine data from multiple studies to boost power, individual cohorts may still suffer from moderate sizes, potentially missing true genetic associations or underestimating their impact .
The rs73292433 variant is associated with the ETV6 gene, which encodes an E26 transformation-specific (ETS) family transcription factor. ETV6 is a master regulator of gene expression, playing a critical role in hematopoiesis, the process of blood cell formation, and is also involved in angiogenesis, the formation of new blood vessels. Its function is essential for proper development and maintenance of the blood system, and disruptions in ETV6activity are frequently implicated in various types of leukemia and other hematological disorders. Ifrs73292433 leads to a histidine change within theETV6protein, it could significantly impact the protein’s ability to bind DNA, interact with co-factors, or maintain its structural integrity. This alteration could disrupt the precise regulation of target genes involved in cell proliferation, differentiation, or programmed cell death, contributing to abnormal blood cell development or an increased risk for cancer. Understanding such variants and their impact on crucial proteins like ETV6 is vital for elucidating disease mechanisms and identifying potential therapeutic targets.[4]
Biological Background
Section titled “Biological Background”Protein Structure, Function, and Amino Acid Variants
Section titled “Protein Structure, Function, and Amino Acid Variants”Genetic variations can lead to alterations in protein sequences, often through nonsynonymous variants or missense mutations that result in a change of a single amino acid residue. Such substitutions at critical positions can significantly modify a protein’s structure and function, leading to diverse physiological outcomes.[3]For instance, a valine to isoleucine substitution in Hemoglobin S Antilles reduces its solubility, causing sickle cell disease in individuals who are heterozygous for the variant.[5]Similar valine to isoleucine changes have been implicated in conditions like familial Alzheimer’s disease, linked to a missense mutation in the amyloid precursor protein gene, and radiographic joint destruction in rheumatoid arthritis, associated with a Val58Ile polymorphism in chondromodulin-II.[6]These examples highlight how subtle changes in amino acid composition can disrupt protein integrity and lead to clinical phenotypes.
Further examples of specific amino acid changes illustrate their broad impact across various critical biomolecules. In theABO blood group system, the rs8176746 variant involves a leucine to methionine amino acid change that is found on all B haplotypes, fundamentally altering the protein’s characteristics.[1] Another significant change is the R325W polymorphism (rs13266634 ) in SLC30A8, where an arginine is replaced by a tryptophan. This particular variant has been shown to be protective against type 2 diabetes and influences insulin secretion, demonstrating how a single amino acid alteration can have a profound effect on metabolic regulation and disease susceptibility.[2] Moreover, common nonsynonymous variants, such as those in GLUT9affecting serum uric acid levels, underscore how altered protein function can disrupt homeostatic processes.[3]
Genetic Regulation through Gene Expression and Splicing
Section titled “Genetic Regulation through Gene Expression and Splicing”Beyond direct amino acid substitutions, genetic mechanisms, including variations in regulatory elements and gene expression patterns, profoundly influence protein function. One crucial regulatory process is alternative splicing, where different messenger RNA (mRNA) isoforms can be produced from a single gene, leading to various protein products or altering protein levels. For example, an intronic variant,rs3846662 , located downstream of exon13 in the HMGCR gene, significantly affects the efficiency of alternative splicing of exon13. [7] This variant’s minor allele leads to significantly lower expression levels of the alternatively spliced Δexon13 HMGCR mRNA, thereby modulating the overall amount of functional HMGCR protein. [7]
The regulation of gene splicing in mammals involves both cis-acting auxiliary element sequences within the pre-mRNA and trans-acting cellular splicing factors, which include various protein families. [7] The observed differences in HMGCR mRNA splicing between different alleles of rs3846662 suggest that this SNP might be located in a binding motif for a splice auxiliary protein, where allele status alters the protein’s binding affinity.[7] This intricate regulatory network ensures that protein expression is finely tuned, and disruptions, such as those impacting BCL11Aand its influence on fetal hemoglobin levels, can have significant systemic consequences.[8]
Molecular and Metabolic Pathway Integration
Section titled “Molecular and Metabolic Pathway Integration”Changes in protein structure, function, or expression levels directly impact molecular and metabolic pathways, disrupting cellular homeostasis. The HMGCR gene, for instance, encodes HMG-CoA reductase, a critical enzyme in cholesterol biosynthesis. Altered alternative splicing of HMGCR can decrease its activity, leading to lower cellular cholesterol synthesis. [7] In response, cells may increase cholesterol uptake from the plasma via the LDL-receptor pathway to maintain intracellular cholesterol homeostasis, illustrating a compensatory mechanism within the metabolic network. [7]
Similarly, other key biomolecules play vital roles in metabolic regulation. Variations in GLUT9can affect serum uric acid levels, implicating its role in uric acid transport and metabolism.[3] The enzyme hexokinase (HK1), which catalyzes the initial, rate-limiting step in erythrocyte glucose metabolism, can have its activity modulated by genetic variations, thereby affecting glycated hemoglobin levels.[2] Furthermore, SLC30A8functions as a zinc transporter in pancreatic beta cells, providing zinc essential for insulin maturation and storage; its R325W polymorphism influences insulin secretion, demonstrating the intricate connection between genetic variants, enzyme function, and systemic glucose metabolism.[2]The comprehensive study of metabolite profiles in human serum reveals that genetic variants can indeed associate with changes in the homeostasis of key lipids, carbohydrates, and amino acids.[9]
Pathophysiological Processes and Clinical Outcomes
Section titled “Pathophysiological Processes and Clinical Outcomes”Disruptions in protein function and metabolic pathways, whether due to amino acid substitutions or altered gene regulation, can culminate in various pathophysiological processes and clinical phenotypes. For example, the aforementioned valine to isoleucine substitution in Hemoglobin S Antilles directly causes sickle cell disease, a severe hematological disorder.[5]Similarly, missense mutations in the amyloid precursor protein gene are linked to familial Alzheimer’s disease, a neurodegenerative condition.[6]These examples highlight how specific protein changes can initiate distinct disease mechanisms at the molecular level, which then manifest as organ-specific and systemic consequences.
The systemic impact of such genetic variations is further evident in metabolic disorders and inflammatory conditions. The rs3846662 variant affecting HMGCRsplicing, which results in lower LDL-cholesterol levels, underscores its relevance to cardiovascular health.[7]The Val58Ile polymorphism in chondromodulin-II is associated with radiographic joint destruction in rheumatoid arthritis, demonstrating a link between genetic variation and chronic inflammatory disease progression.[10] Moreover, the protective effect of the SLC30A8R325W polymorphism against type 2 diabetes illustrates how genetic factors can modulate disease risk, influencing homeostatic balance and potentially offering targets for pharmacological interventions.[2]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs7982187 | GPR12 - FGFR1OP2P1 | histidine change measurement |
| rs73292433 | ETV6 | histidine change measurement |
References
Section titled “References”[1] Melzer D, et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet, 2008.
[2] Pare, G., et al. “Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women.” PLoS Genetics, vol. 4, no. 7, 2008, e1000118.
[3] McArdle, Patrick F., et al. “Association of a Common Nonsynonymous Variant in GLUT9with Serum Uric Acid Levels in Old Order Amish.”Arthritis Rheum, vol. 58, no. 9, 2008, pp. 2874-81.
[4] Yang Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, 2007.
[5] Monplaisir, N., et al. “Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes.”Proc Natl Acad Sci U S A. 1986.
[6] Goate, Alison, et al. “Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease.”Nature. 1991.
[7] Burkhardt, Ralph, et al. “Common SNPs in HMGCR in Micronesians and Whites Associated with LDL-Cholesterol Levels Affect Alternative Splicing of Exon13.” Arterioscler Thromb Vasc Biol, vol. 28, no. 11, 2008, pp. 1968-75.
[8] Uda, Manuela, et al. “Genome-Wide Association Study Shows BCL11AAssociated with Persistent Fetal Hemoglobin and Amelioration of the Phenotype of Beta-Thalassemia.”Proc Natl Acad Sci U S A, vol. 105, no. 5, 2008, pp. 1620-25.
[9] Gieger, Christian, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet. 2008.
[10] Graessler, Jürgen, et al. “Association of chondromodulin-II Val58Ile polymorphism with radiographic joint destruction in rheumatoid arthritis.”J Rheumatol. 2005.