Recombinant Human Transmembrane protein 91 (TMEM91)

What is TMEM91 and what cellular functions has it been associated with?

TMEM91 (Transmembrane Protein 91) is a member of the transmembrane protein family that mediates numerous human physiological processes. According to current research, TMEM91 appears to be involved in the regulation of cell migration and invasion, participates in the construction of ion channels, and plays a role in immune response mechanisms . The protein is encoded by the TMEM91 gene located on chromosomal region 19q13.2. While much of the current research on TMEM family members has focused on cancer contexts, studies are beginning to explore its potential roles in other conditions, including autoimmune diseases.

How do TMEM91 copy number variations (CNVs) compare between normal populations and those with autoimmune conditions?

Research has investigated TMEM91 CNVs in patients with autoimmune thyroid diseases (AITD) compared to healthy controls. In a study of 158 AITD patients and 181 controls, the distribution of TMEM91 CNVs showed that 93.67% of patients had normal copy numbers, 5.70% had copy number losses, and 0.63% had copy number gains. In the control group, 97.24% had normal copy numbers, 2.21% had losses, and 0.55% had gains . Although there appeared to be a trend toward more frequent CNV loss in AITD patients (5.70% vs. 2.21%), this difference did not reach statistical significance (p=0.095) . This suggests that while TMEM91 CNVs might play some role in AITD susceptibility, the effect may be subtle or require larger sample sizes to detect.

What experimental methods are typically used to identify and quantify TMEM91 gene copy numbers?

To identify and quantify TMEM91 gene copy numbers, researchers have employed several methodologies, with real-time PCR being a primary approach. In published research, TMEM91 copy numbers were quantified using real-time PCR performed on systems such as the ABI 7500 Fast System, using Fast-Start Universal SYBR Green Master .

For primer design, online tools like Primer 3.0 software are utilized based on sequence data obtained from the NCBI database. Specific primers for TMEM91 have been documented (forward primer: 5′-TGCTGCCTTGGGATTCCTTA-3′ and reverse primer: 5′-AGCAGGCTCATGACTCACTT-3′) .

The comparative Ct method (ΔΔCt) is commonly employed, using a single-copy control gene such as RPPH1 and a reference genomic DNA of known copy number. In quantification analysis, copy numbers ≤1.5 are typically considered to indicate losses, while those ≥2.5 are considered gains .

What is the relationship between TMEM91 and SIRPB1 CNVs in autoimmune disease contexts?

Research has revealed an interesting correlation between TMEM91 and SIRPB1 copy number variations in the context of autoimmune thyroid diseases. According to Spearman's rho analysis of 158 AITD patients, a significant correlation exists between TMEM91 and SIRPB1 CNVs (coefficient correlation, rs = 0.292, p < 0.001) . This correlation suggests potential functional relationships or common regulatory mechanisms affecting both genes.

How might environmental factors interact with TMEM91 genetic variations in disease pathogenesis?

The interaction between genetic variations like TMEM91 CNVs and environmental factors presents a critical area for autoimmune disease research. In studies of AITD, environmental factors such as iodine exposure have been identified as significant risk factors. When researchers investigated possible interactions between candidate gene CNVs (including TMEM91) and urinary iodine levels, no significant associations were detected .

• Limited sample size may have restricted statistical power to detect complex gene-environment interactions

• The occurrence of CNVs may increase individual susceptibility to AITD, with disease manifesting only when susceptible individuals are exposed to environmental triggers

• Multiple factors working together (genetic variations, iodine exposure, infection, stress) may mask simple correlations between any two factors

This area represents an important direction for future research, as understanding such interactions could significantly impact disease prevention strategies.

What mechanisms might explain TMEM91's potential role in autoimmune conditions?

While specific mechanisms linking TMEM91 to autoimmune conditions are still being elucidated, several hypotheses can be formulated based on known functions of transmembrane proteins and current research:

• Immune cell signaling: As a member of the transmembrane protein family involved in immune responses, TMEM91 may participate in immune cell signaling pathways that influence tolerance mechanisms or inflammatory responses.

• Cell migration regulation: Given TMEM91's reported role in regulating cell migration, alterations in its function could affect immune cell trafficking to tissues targeted in autoimmune conditions.

• Ion channel contribution: TMEM91's possible role in ion channel construction could influence cellular activation thresholds in immune cells or affect antigen-presenting cell function.

• Genetic interactions: The correlation between TMEM91 and SIRPB1 CNVs suggests possible functional interactions, with SIRPB1 being an immune-related gene already implicated in autoimmune thyroid diseases .

Research has found that while TMEM91 CNVs alone did not show significant association with AITD, multivariate analysis including both TMEM91 and SIRPB1 identified SIRPB1 as an independent risk factor (OR = 3.66, 95% CI: 1.40-9.58, p = 0.008) . This suggests complex genetic interactions may be at play.

What approaches should researchers use to identify novel TMEM91 interactions and functional pathways?

To investigate TMEM91 interactions and functional pathways, researchers should consider employing multiple complementary approaches:

• Chromosome microarray analysis: This method has been successfully used to identify TMEM91 CNVs in human samples. For example, the Affymetrix CytoScanTM HD platform, which contains more than 2.6 million copy number markers, can be utilized following manufacturer protocols for amplification, hybridization, washing, and staining steps .

• Real-time PCR validation: Following identification of variations through microarray, real-time PCR provides a reliable method for validation and quantification in larger sample sets. This approach should include appropriate controls and standardized cutoffs for determining copy number status .

• Correlation analysis: Statistical methods such as Spearman's correlation can help identify relationships between TMEM91 and other genes of interest, as demonstrated in the correlation found with SIRPB1 (rs = 0.292, p < 0.001) .

• Multivariate analysis: When examining disease associations, multivariate logistic regression models should be employed to account for confounding factors. These analyses should adjust for relevant demographic and clinical variables, as seen in studies adjusting for sex, age, and BMI when examining TMEM91 in AITD .

How should researchers design experiments to study TMEM91 in relation to autoimmune disease mechanisms?

When designing experiments to study TMEM91 in autoimmune disease contexts, researchers should consider the following methodological approaches:

• Case-control design with adequate sample sizing: Studies should include well-matched case and control groups. Previous research utilized 158 patients and 181 controls, finding some trends but limited statistical significance for TMEM91, suggesting larger samples may be necessary .

• Comprehensive genetic analysis: Beyond CNVs, consider examining single nucleotide polymorphisms, expression levels, and epigenetic modifications of TMEM91.

• Environmental factor assessment: Measure and account for relevant environmental triggers. In AITD studies, urinary iodine concentration was measured and categorized (≤100 μg/L, 100-200 μg/L, 200-300 μg/L, >300 μg/L) to assess potential interactions with genetic factors .

• Statistical interaction analysis: Employ appropriate statistical models to detect gene-environment interactions. This is particularly important as previous research found no significant interactions between TMEM91 CNVs and iodine levels, but suggested multiple factors may obscure simple associations .

The table below summarizes a methodological approach used in previous research examining TMEM91 CNVs in relation to iodine levels:

*Adjusted for sex, age, and BMI

What quality control measures are essential when working with recombinant TMEM91 protein preparations?

While the search results don't provide specific information about recombinant TMEM91 protein preparations, we can extrapolate quality control measures from standard practices for recombinant proteins (such as the EGF protein in search result ) and the known characteristics of TMEM91:

• Expression verification: Confirm correct protein expression using methods like Western blot with antibodies specific to TMEM91 or to epitope tags engineered into the recombinant construct.

• Purity assessment: Evaluate protein purity through SDS-PAGE and other chromatographic methods to ensure preparations are free from contaminating proteins and endotoxins.

• Functional validation: Develop and implement functional assays based on TMEM91's known roles in cell migration, ion channel function, or immune response to verify that the recombinant protein retains biological activity.

• Stability testing: Assess protein stability under various storage conditions to establish appropriate handling protocols for maintaining activity.

• Batch consistency: Implement rigorous lot-to-lot testing to ensure consistent performance in experimental applications, similar to the approach used for other recombinant proteins where multiple independent lots are tested to demonstrate consistency .

What are the most promising areas for future TMEM91 research in autoimmunity?

Based on current findings, several promising research directions for TMEM91 in autoimmunity include:

• Expanded genetic association studies: Larger cohorts across different populations would help clarify the significance of TMEM91 CNVs in autoimmune conditions. Current research showing a trend toward increased CNV loss in AITD patients (5.70% vs. 2.21%, p=0.095) suggests potential associations that might reach significance with greater statistical power .

• Functional characterization: More detailed studies of TMEM91's physiological roles in immune cell function, particularly in relation to autoimmune disease mechanisms, would fill significant knowledge gaps.

• Gene-gene interaction studies: Further exploration of the significant correlation observed between TMEM91 and SIRPB1 CNVs (rs = 0.292, p < 0.001) could uncover important regulatory networks relevant to autoimmunity .

• Gene-environment interaction mechanisms: Despite finding no significant interaction between TMEM91 CNVs and iodine levels, researchers have suggested that multiple factors may be at play and that larger studies with more comprehensive environmental assessments are needed .

• Therapeutic targeting potential: Investigating whether modulation of TMEM91 function could provide therapeutic benefits in autoimmune conditions represents an area for long-term translational research.

How might integration of TMEM91 data with broader immunogenomic datasets advance our understanding of autoimmunity?

Integrating TMEM91 data with broader immunogenomic datasets could provide valuable insights through:

• Pathway enrichment analysis: Identifying biological pathways where TMEM91 interacts with other immune-related genes could reveal its place in larger regulatory networks governing immune function.

• Multi-omics integration: Combining TMEM91 genetic data with transcriptomic, proteomic, and epigenomic datasets could help elucidate regulatory mechanisms and functional consequences of genetic variations.

• Network medicine approaches: Positioning TMEM91 within disease-specific protein-protein interaction networks might identify its contribution to disease modules and suggest potential therapeutic interventions.

• Comparative autoimmune disease genomics: Examining TMEM91's role across multiple autoimmune conditions could reveal common mechanisms or disease-specific effects that inform understanding of autoimmunity more broadly.

• Precision medicine applications: Correlating TMEM91 variations with clinical outcomes might ultimately contribute to better patient stratification and personalized therapeutic approaches in autoimmune conditions.