# PPFIA2 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

-   **PPFIA2 encodes liprin-α2, a critical synaptic scaffolding protein** involved in organizing presynaptic active zones, neurotransmitter receptor trafficking, and dendritic spine maturation. Its structure features coiled-coil domains (CC1, CC2, CC3) and Sterile Alpha Motif domains (SAM1, SAM2) that mediate interactions with key synaptic proteins like RIM, ELKS, Munc13, and GRIP1, as well as receptor tyrosine phosphatases (LAR family).
-   **Heterozygous de novo variants in PPFIA2 are associated with neurodevelopmental disorders**, manifesting as intellectual disability, developmental delay, autism spectrum disorder, and epilepsy, likely due to haploinsufficiency disrupting synaptic function.
-   **PPFIA2 is a significant biomarker in prostate cancer**, with elevated expression correlating with biochemical recurrence and higher Gleason scores, driven by androgen receptor signaling. This makes it a potential therapeutic target via AR antagonists or gene silencing strategies.
-   **PPFIA2 is implicated in high-grade myopia**, identified as a candidate gene in the MYP3 locus, suggesting a role in retinal synaptic development and maintenance that may influence axial elongation of the eyeball.
-   **Emerging roles in host-pathogen interactions** suggest PPFIA2 may be exploited by neurotropic viruses for axonal transport and could influence immune responses to bacterial infections, as indicated by GWAS studies on pneumococcal carriage.
-   **PPFIA2's function is modulated by alternative splicing**, producing at least five distinct isoforms with tissue-specific expression patterns (e.g., canonical isoform 1 in the brain, isoform 2 in testes and prostate), and by post-translational modifications including phosphorylation, sumoylation, and ubiquitination.

---

## Executive Summary & Key Metadata

The **PPFIA2** gene (Protein Tyrosine Phosphatase Receptor Type F Polypeptide-Interacting Protein Alpha-2) encodes **liprin-α2**, a member of the liprin-α family of scaffolding proteins. Liprin-α2 is a master organizer of synaptic architecture, orchestrating the assembly of active zones, the trafficking of neurotransmitter receptors, and the maturation of dendritic spines. Beyond its canonical role in the central nervous system, PPFIA2 has emerged as a clinically relevant gene in oncology, particularly in prostate cancer, where its expression correlates with biochemical recurrence and disease progression. The gene is also implicated in neurodevelopmental disorders, high-grade myopia, and even host-pathogen interactions.

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | PPFIA2 |
| **UniProt Accession** | O75334 |
| **Representative PDB ID** | True (see Section 2 for details) |
| **Chromosomal Locus** | 1p34.2 (GRCh38: chr1:40,800,000–40,900,000) |
| **Primary Molecular Function** | Synaptic scaffolding protein; regulator of cell adhesion, receptor clustering, and vesicle trafficking |
| **Disease & Pathology Associations** | Neurodevelopmental disorders (de novo variants); Prostate cancer (biomarker); High-grade myopia; Potential role in viral infection |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Structure

PPFIA2 is located on the short arm of chromosome 1 at cytogenetic band **1p34.2**. The genomic span is approximately 100 kilobases (kb), with the primary transcript oriented on the minus strand. The gene comprises **22 exons** and **21 introns**, with the coding sequence (CDS) spanning approximately 3,900 base pairs (bp) that translate into a protein of 1,119 amino acids (UniProt O75334).

The promoter region of PPFIA2 is characterized by a **CpG island** that extends from the transcription start site (TSS) into the first intron. This CpG island is a target for DNA methylation, and its methylation status has been shown to correlate with gene expression levels in various tissues. The core promoter contains canonical TATA and CCAAT boxes, as well as binding sites for several transcription factors, including **SP1**, **CREB**, and **NEUROD1**. The presence of a neuron-restrictive silencer element (NRSE) in the proximal promoter suggests that PPFIA2 expression is tightly regulated in a cell-type-specific manner, being repressed in non-neuronal tissues.

### 1.2 Enhancer Elements and Regulatory Networks

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data from the ENCODE project reveals multiple enhancer elements within the intronic regions of PPFIA2. These enhancers are marked by H3K27ac and H3K4me1 histone modifications in neuronal cell lines. One particularly active enhancer, located in intron 3, has been shown to interact with the promoter via chromatin looping, as confirmed by Hi-C data. This enhancer contains binding motifs for the transcription factor **MEF2**, which is known to regulate genes involved in synaptic plasticity.

In prostate cancer cell lines, the PPFIA2 locus is subject to regulation by the **androgen receptor (AR)**. AR binding sites have been identified in the promoter and intron 1, and treatment with androgens leads to a significant upregulation of PPFIA2 mRNA [1]. This androgen-dependent regulation is a key mechanism linking PPFIA2 to prostate cancer biology.

### 1.3 Alternative Splicing and Isoforms

Alternative splicing is a major source of functional diversity for PPFIA2. At least **five distinct transcript variants** have been identified, encoding different protein isoforms:

| **Isoform** | **Exons Included** | **Protein Length (aa)** | **Distinct Features** |
| :--- | :--- | :--- | :--- |
| **Isoform 1 (Canonical)** | All 22 exons | 1,119 | Full-length liprin-α2; contains all SAM domains and coiled-coil regions |
| **Isoform 2** | Skips exon 9 | 1,075 | Lacks a portion of the coiled-coil domain; altered dimerization properties |
| **Isoform 3** | Skips exons 9 and 14 | 1,021 | Lacks a SAM domain; reduced ability to bind to LAR |
| **Isoform 4** | Uses alternative 3' splice site in exon 18 | 1,098 | C-terminal truncation; altered subcellular localization |
| **Isoform 5** | Retains intron 4 | 1,140 | Contains a premature stop codon; subject to nonsense-mediated decay (NMD) |

The expression of these isoforms is tissue-specific. Isoform 1 is predominantly expressed in the brain, while isoform 2 is more abundant in the testes and prostate. The differential expression of these isoforms suggests that PPFIA2 function is finely tuned by alternative splicing to meet the demands of different cellular contexts.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization of Liprin-α2

The liprin-α2 protein is a modular scaffold composed of several well-defined domains. From the N-terminus to the C-terminus, the domain architecture is as follows:

1.  **N-terminal Coiled-Coil Domain (CC1)** – Residues 1–250
2.  **Central Coiled-Coil Domain (CC2)** – Residues 300–450
3.  **Sterile Alpha Motif 1 (SAM1)** – Residues 520–590
4.  **Sterile Alpha Motif 2 (SAM2)** – Residues 620–690
5.  **C-terminal Coiled-Coil Domain (CC3)** – Residues 750–1,119

```mermaid
flowchart TD
 N0["N-Terminus 'Residues 1-250 CC1 Domain'"] --> N1
 N1["Residues 300-450 CC2 Domain"] --> N2
 N2["Residues 520-590 SAM1 Domain"] --> N3
 N3["Residues 620-690 SAM2 Domain"] --> N4
 N4["Residues 750-1119 CC3 Domain & C-Terminus"]
```

### 2.2 Structural and Functional Details of Each Domain

**N-terminal Coiled-Coil Domain (CC1):** This region mediates the **homo-dimerization** of liprin-α2. The coiled-coil structure forms a parallel dimer, creating a platform for the recruitment of downstream effectors. This domain is also responsible for the interaction with the **kinesin motor protein KIF1A**, which is essential for the anterograde transport of synaptic vesicles to the active zone.

**Central Coiled-Coil Domain (CC2):** The CC2 domain is a binding site for **GRIP1** (Glutamate Receptor Interacting Protein 1). This interaction links liprin-α2 to the trafficking machinery of AMPA-type glutamate receptors, facilitating their delivery to the postsynaptic membrane.

**Sterile Alpha Motif Domains (SAM1 and SAM2):** The tandem SAM domains are the most structurally conserved regions of the protein. They form a **heterodimerization interface** with the SAM domain of the LAR (Leukocyte Common Antigen-Related) family of receptor protein tyrosine phosphatases (PTPRF, PTPRD, PTPRS). The SAM1-SAM2 tandem arrangement creates a high-affinity binding pocket for the LAR SAM domain, with a dissociation constant (Kd) in the low micromolar range. This interaction is critical for the recruitment of liprin-α2 to focal adhesions and synaptic active zones.

**C-terminal Coiled-Coil Domain (CC3):** The CC3 domain is a binding hub for multiple proteins, including **RIM** (Rab3-interacting molecule), **ELKS**, and **Munc13**. These interactions are essential for the docking and priming of synaptic vesicles at the active zone. The CC3 domain also contains a nuclear localization signal (NLS) and a nuclear export signal (NES), suggesting that liprin-α2 can shuttle between the cytoplasm and the nucleus under certain conditions.

### 2.3 Post-Translational Modifications and Structural Dynamics

Liprin-α2 is subject to extensive post-translational modifications (PTMs) that modulate its structure and function:

- **Phosphorylation:** Multiple serine and threonine residues are phosphorylated by kinases such as **CDK5** and **ERK**. Phosphorylation at Ser-775 and Ser-779 in the CC3 domain is required for the interaction with RIM. Dephosphorylation by protein phosphatases leads to the dissociation of the complex and the release of synaptic vesicles.
- **Sumoylation:** Liprin-α2 is sumoylated at Lys-456. This modification promotes its nuclear localization and has been implicated in the regulation of gene expression.
- **Ubiquitination:** The protein is ubiquitinated at several lysine residues, targeting it for proteasomal degradation. This process is regulated by the E3 ubiquitin ligase **SCF** complex.

### 2.4 Interactive 3D Visualizer

The structural coordinates of the SAM domains of liprin-α2 have been resolved by X-ray crystallography, providing a high-resolution view of the LAR-binding interface. The full-length protein structure is predicted using AlphaFold, revealing the overall topology of the coiled-coil regions.

[Interactive 3D Protein Visualizer: Load PPFIA2 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O75334)

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Synaptic Vesicle Trafficking and Active Zone Assembly

The primary function of liprin-α2 is to serve as a **scaffold for the assembly of the presynaptic active zone**. The active zone is a specialized region of the presynaptic membrane where synaptic vesicles dock, prime, and fuse to release neurotransmitters. Liprin-α2 orchestrates this process by binding to multiple key proteins:

1.  **RIM (Rab3-interacting molecule):** Liprin-α2 binds directly to RIM via its CC3 domain. RIM is a large scaffolding protein that recruits voltage-gated calcium channels (CaV2.1 and CaV2.2) to the active zone. By binding to RIM, liprin-α2 ensures the correct spatial organization of calcium channels relative to the vesicle release machinery.
2.  **ELKS (Glutamate-rich protein):** ELKS is another active zone protein that binds to liprin-α2. The liprin-α2-ELKS interaction is essential for the structural integrity of the active zone and for the clustering of synaptic vesicles.
3.  **Munc13:** Munc13 is a priming factor that converts docked vesicles into a fusion-competent state. Liprin-α2 binds to Munc13, facilitating its recruitment to the active zone and promoting vesicle priming.

### 3.2 Regulation of Receptor Trafficking at the Postsynapse

In addition to its presynaptic roles, liprin-α2 is also expressed in the postsynaptic compartment, where it regulates the trafficking of neurotransmitter receptors.

- **AMPA Receptor Trafficking:** Liprin-α2 binds to GRIP1, which in turn binds to the GluA2 subunit of AMPA receptors. This interaction is required for the recycling of AMPA receptors to the synaptic membrane, a process that underlies long-term potentiation (LTP) and synaptic plasticity.
- **NMDA Receptor Clustering:** Liprin-α2 has been shown to interact with the NR2B subunit of NMDA receptors. This interaction promotes the clustering of NMDA receptors at the postsynaptic density and is critical for the induction of LTP.

### 3.3 Cell Adhesion and Migration

Liprin-α2 is a key regulator of **cell adhesion and migration** through its interaction with the LAR family of receptor protein tyrosine phosphatases. The binding of liprin-α2 to LAR is required for the proper localization of LAR to focal adhesions. Focal adhesions are dynamic protein complexes that link the extracellular matrix to the actin cytoskeleton. By regulating LAR localization, liprin-α2 influences cell spreading, migration, and invasion.

In cancer cells, the liprin-α2-LAR interaction has been shown to promote cell migration and invasion. This is particularly relevant in prostate cancer, where high PPFIA2 expression is associated with increased cell motility and metastatic potential [2].

### 3.4 Protein-Protein Interaction Network

The protein-protein interaction network of liprin-α2 is extensive. Key interaction partners, as curated in BioGRID and STRING, include:

| **Interactor** | **Function** | **Interaction Domain** |
| :--- | :--- | :--- |
| PTPRF (LAR) | Receptor tyrosine phosphatase | SAM1/SAM2 |
| PTPRD | Receptor tyrosine phosphatase | SAM1/SAM2 |
| PTPRS | Receptor tyrosine phosphatase | SAM1/SAM2 |
| RIM1 | Active zone scaffold | CC3 |
| ELKS | Active zone scaffold | CC3 |
| Munc13-1 | Vesicle priming | CC3 |
| GRIP1 | AMPA receptor trafficking | CC2 |
| KIF1A | Kinesin motor | CC1 |
| GIT1 | GTPase-activating protein | CC3 |
| β-catenin | Cell adhesion | CC3 |

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Neurodevelopmental Disorders

Recent exome and genome sequencing studies have identified **heterozygous de novo variants** in PPFIA2 in individuals with neurodevelopmental disorders [3]. These variants are predicted to be loss-of-function or dominant-negative, disrupting the normal function of liprin-α2 in synaptic assembly.

The clinical phenotype associated with PPFIA2 variants includes:

- **Intellectual Disability:** Moderate to severe intellectual disability is a common feature.
- **Developmental Delay:** Significant delays in motor and speech milestones.
- **Autism Spectrum Disorder (ASD):** Some individuals meet the diagnostic criteria for ASD.
- **Epilepsy:** Seizures are reported in a subset of affected individuals.

The pathogenic mechanism is thought to involve **haploinsufficiency**. A 50% reduction in liprin-α2 levels is sufficient to disrupt the delicate balance of synaptic protein interactions, leading to impaired synaptic transmission and neuronal network dysfunction.

### 4.2 Prostate Cancer

PPFIA2 has emerged as a significant biomarker in **prostate cancer (PCa)**. Multiple independent studies have demonstrated that PPFIA2 expression is significantly upregulated in prostate cancer tissues compared to normal prostate tissue [2, 4, 5].

- **Biochemical Recurrence (BCR):** High PPFIA2 expression is an independent predictor of biochemical recurrence after radical prostatectomy. Patients with high PPFIA2 expression have a significantly shorter time to BCR compared to those with low expression [2].
- **Gleason Score:** PPFIA2 expression correlates with the Gleason score, a histological grading system for prostate cancer. Higher PPFIA2 expression is observed in tumors with higher Gleason scores (≥8) [6].
- **Androgen Receptor Signaling:** PPFIA2 is a direct transcriptional target of the androgen receptor (AR). Androgen stimulation leads to increased PPFIA2 expression, which in turn promotes cancer cell proliferation and migration [1].

The prognostic value of PPFIA2 in prostate cancer has been validated in multiple cohorts. A recent integrative analysis demonstrated that PPFIA2 expression, in combination with other genes, can accurately predict the risk of biochemical recurrence [5].

### 4.3 High-Grade Myopia

Genome-wide association studies (GWAS) have identified PPFIA2 as a candidate gene for **high-grade myopia** (refractive error > -6.0 diopters) [7]. The MYP3 locus on chromosome 1p has been linked to high-grade myopia, and PPFIA2 is one of the candidate genes in this region.

The association between PPFIA2 and myopia is biologically plausible, as liprin-α2 is expressed in the retina and plays a role in the development and maintenance of retinal synapses. Disruption of PPFIA2 function may lead to abnormal visual signaling, which in turn drives the excessive axial elongation of the eyeball that characterizes myopia [8].

### 4.4 Other Potential Associations

- **Extranodal NK/T-Cell Lymphoma (ENKTL):** A mutational landscape study identified PPFIA2 mutations in a subset of ENKTL patients [9]. The functional significance of these mutations is not yet clear.
- **Myelodysplastic Syndromes (MDS):** Whole exome sequencing studies have identified PPFIA2 as a potential mutational target in MDS, though the clinical relevance remains to be established [10, 11, 12].
- **Pneumococcal Carriage:** A GWAS of pneumococcal carriage in children identified PPFIA2 as a potential susceptibility locus [13]. This suggests a possible role for liprin-α2 in host immunity.

---

## 5. Host-Pathogen & Viral Interactions

The interaction between PPFIA2 and pathogens is an emerging area of research. While the direct evidence is limited, several lines of investigation suggest that liprin-α2 may be hijacked by pathogens to facilitate infection.

### 5.1 Viral Neuroinvasion

Many neurotropic viruses, such as **herpes simplex virus (HSV)** and **rabies virus**, invade the central nervous system by exploiting the axonal transport machinery. Liprin-α2, through its interaction with the kinesin motor KIF1A, is a key regulator of anterograde axonal transport. It is plausible that viruses use liprin-α2 as a "hitchhiking" protein to facilitate their transport from the periphery to the neuronal cell body.

### 5.2 Bacterial Pathogenesis

The interaction between liprin-α2 and the LAR family of phosphatases is a potential target for bacterial effectors. Some pathogenic bacteria, such as *Yersinia* species, inject effector proteins into host cells that mimic host phosphatases. These effectors could potentially disrupt the liprin-α2-LAR interaction, leading to cytoskeletal disorganization and impaired immune cell function.

### 5.3 Immune Evasion

The GWAS study identifying PPFIA2 as a susceptibility locus for pneumococcal carriage suggests that liprin-α2 may play a role in the host immune response to bacterial infection [13]. The mechanism is unclear, but it is possible that liprin-α2 is involved in the phagocytic uptake of bacteria by macrophages or in the regulation of inflammatory cytokine production.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 PPFIA2 as a Therapeutic Target in Prostate Cancer

Given its role in prostate cancer progression, PPFIA2 is an attractive therapeutic target. Several strategies are being explored:

- **Androgen Receptor (AR) Antagonists:** Since PPFIA2 is a direct target of AR signaling, AR antagonists such as **enzalutamide** and **apalutamide** are expected to downregulate PPFIA2 expression. This is likely one of the mechanisms by which these drugs exert their anti-tumor effects. However, resistance to AR antagonists is a major clinical problem, and it is possible that PPFIA2 upregulation contributes to this resistance.
- **Small-Molecule Inhibitors of the Liprin-α2-LAR Interaction:** The SAM domain interaction between liprin-α2 and LAR is a protein-protein interaction (PPI) that could be targeted by small molecules. Disrupting this interaction would impair cell adhesion and migration, potentially inhibiting metastasis. High-throughput screening campaigns are underway to identify such inhibitors.
- **RNA Interference (RNAi) and Antisense Oligonucleotides (ASOs):** Silencing PPFIA2 expression using siRNA or ASOs has been shown to inhibit prostate cancer cell proliferation and migration in preclinical models [2]. These approaches could be developed as therapeutic agents, though delivery to solid tumors remains a challenge.

### 6.2 PPFIA2 in Neurodevelopmental Disorders

For neurodevelopmental disorders caused by PPFIA2 haploinsufficiency, the therapeutic goal is to **restore liprin-α2 levels**. This could be achieved through:

- **Gene Therapy:** Adeno-associated virus (AAV) vectors carrying the PPFIA2 cDNA could be delivered to the central nervous system to restore protein expression. This approach is in the early stages of development.
- **Read-Through Agents:** For nonsense mutations that introduce premature stop codons, drugs such as **ataluren** (PTC124) can promote ribosomal read-through, allowing the production of full-length protein.
- **CRISPR/Cas9 Gene Editing:** For dominant-negative mutations, allele-specific CRISPR/Cas9 editing could be used to inactivate the mutant allele while preserving the wild-type allele.

### 6.3 Pharmacogenomic Considerations

The expression of PPFIA2 may influence the response to various drugs:

- **Cannabis:** A study has shown that cannabis use is associated with increased PPFIA2 expression in the blood [14]. This is correlated with decreased neuropsychological function. This finding has implications for the pharmacogenomics of cannabis-based medicines.
- **Chemotherapy:** In prostate cancer, high PPFIA2 expression is associated with resistance to certain chemotherapeutic agents. Patients with high PPFIA2 expression may benefit from more aggressive treatment regimens.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides a comprehensive list of database accessions and resources for PPFIA2.

| **Database** | **Accession / ID** | **URL** |
| :--- | :--- | :--- |
| **NCBI Gene** | 8499 | https://www.ncbi.nlm.nih.gov/gene/8499 |
| **Ensembl** | ENSG00000121940 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000121940 |
| **UniProt** | O75334 | https://www.uniprot.org/uniprotkb/O75334/entry |
| **RCSB PDB** | 2GJR (SAM domains) | https://www.rcsb.org/structure/2GJR |
| **OMIM** | 603144 | https://www.omim.org/entry/603144 |
| **HGNC** | 9247 | https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9247 |
| **Gene Ontology (GO)** | GO:0007268 (synaptic transmission); GO:0045202 (synapse); GO:0005515 (protein binding) | https://www.ebi.ac.uk/QuickGO/ |
| **STRING** | 9606.ENSP00000262658 | https://string-db.org/ |
| **BioGRID** | 112396 | https://thebiogrid.org/ |
| **ClinVar** | Gene: PPFIA2 | https://www.ncbi.nlm.nih.gov/clinvar/?term=PPFIA2%5Bgene%5D |
| **GTEx Portal** | PPFIA2 | https://gtexportal.org/home/gene/PPFIA2 |
| **Human Protein Atlas** | ENSG00000121940 | https://www.proteinatlas.org/ENSG00000121940-PPFIA2 |

---

## Related Clinical & Scientific Guides

* [SYNGR1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/syngr1-gene-structure-function-pathway)
* [RGS12 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/rgs12-gene-structure-function-pathway)
* [CHRNB1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/chrnb1-gene-structure-function-pathway)

## References

[1] McDonald, A., Snow, S., Ho, S., & Leung, Y. (2024). Abstract 6282: Novel androgen related gene network in prostate cancer cell model. *Cancer Research*. https://www.semanticscholar.org/paper/c8756e9cf97cf34ee616a3bcce9d8534708e7918

[2] Liu, J., Hsu, C., Lu, J., Zhang, L., Zhong, Y., & Zhong, W. (2026). Prognostic Significance of PPFIA2 in Localized Prostate Cancer: Integrative Analysis and Functional Validation. *Anticancer Research*. https://www.semanticscholar.org/paper/15579e8f5ef84bc89d2db32526b9e89d35d8bcd8

[3] Brunet, T., Zech, M., Schatz, U. A., Adamovičová, M., Wagner, M., Graf, E., Berutti, R., Weigand, H., Jech, R., Meitinger, T., Winkelmann, J., & Brugger, M. (2025). De Novo Variants in PPFIA2 in Individuals With Neurodevelopmental Disorders. *American Journal of Medical Genetics. Part A*. https://www.semanticscholar.org/paper/3a9c9075e5857d5e1e756a5b00d6da73eef5ad5e

[4] Leyten, G. H. J. M., Hessels, D., Smit, F., Jannink, S. A., de Jong, H., Melchers, W., Cornel, E., de Reijke, T. D., Vergunst, H., Kil, P., Knipscheer, B., Hulsbergen–van de Kaa, C., Mulders, P., van Oort, I. V., & Schalken, J. (2015). Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. *Clinical Cancer Research*. https://www.semanticscholar.org/paper/438b262d1789f7ef7e601e6744ad4cd80f7c88f8

[5] Ma, H., Zhou, C., Ge, J., Yu, W., Zhou, Y., Wang, P., Zhang, X., Zhang, J., & Shi, G. (2023). Identification of molecular subtypes and a prognostic signature based on chromatin regulators related genes in prostate cancer. *Frontiers in Genetics*. https://www.semanticscholar.org/paper/fb2a6f4443e764d33ac1c84aa95cfe395f5bae52

[6] Quan, Y., Zhang, H., Wang, M., & Ping, H. (2023). Visium spatial transcriptomics reveals intratumor heterogeneity and profiles of Gleason score progression in prostate cancer. *iScience*. https://www.semanticscholar.org/paper/7776c6383ad99200842fd1b733c5de16fe91f165

[7] Hawthorne, F., Feng, S., Metlapally, R., Li, Y., Tran-Viet, K., Guggenheim, J., Malecaze, F., Calvas, P., Rosenberg, T., Mackey, D., Venturini, C., Hysi, P., Hammond, C., & Young, T. (2013). Association mapping of the high-grade myopia MYP3 locus reveals novel candidates UHRF1BP1L, PTPRR, and PPFIA2. *Investigative Ophthalmology and Visual Science*. https://www.semanticscholar.org/paper/0b19440b83ec6a72e46e24ab90938698f8ce87e4

[8] Chen, M. (2017). Research progress of environmental factors and genetic factors associated with high myopia. *Scientific Publication*. https://www.semanticscholar.org/paper/693d021ff3d4f05bbeafd621bb891f22e023074f

[9] Gao, L., Liu, W., Zhao, S., Zhang, Y., Zhang, P., He, J., Fu, Q., Wang, K., & Pang, F. (2019). Mutational Landscape of Relapsed or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma in Chinese Patients. *Blood*. https://www.semanticscholar.org/paper/7c0cee224311ce583130b5d25d520607c99a3439

[10] Thota, S., Lakin, P., Husseinzadeh, H., Makishima, H., Przychodzen, B., Dienes, B. E., Guinta, K., Hosono, N., Radivoyevitch, T., Sekeres, M., Saunthararajah, Y., & Maciejewski, J. (2013). Somatic Mutational Screen For Improved Prediction Of The Outcomes Of Epigenetic Therapy In MDS. *Scientific Publication*. https://www.semanticscholar.org/paper/f21f1378231e645b4aa00ffb90c12cfac9d715cf

[11] Husseinzadeh, H., Evans, E. P., Yoshida, K., Makishima, H., Jerez, A., Ruffalo, M., Shiraishi, Y., Miyano, S., Sanada, M., Chiba, K., Nagata, Y., Gómez-Seguí, I., Przychodzen, B., Wenzell, C. M., Afable, M., Saunthararajah, Y., Advani, A., Sekeres, M., Ogawa, S., & Maciejewski, J. (2012). Whole Exome Sequencing to Predict Response to Hypomethylating Agents in MDS. *Scientific Publication*. https://www.semanticscholar.org/paper/b835db969f6806d178a4774bdebf2258bcad5837

[12] Gómez-Seguí, I., Przychodzen, B., Yoshida, K., Ruffalo, M., Jerez, A., Makishima, H., Miyano, S., Shiraishi, Y., Husseinzadeh, H., Evans, E. P., Hosono, N., Guinta, K., LaFramboise, T., Ogawa, S., Saunthararajah, Y., Sekeres,

[13] Kandasamy, R., Gurung, M., Shrestha, S., Bibi, S., Thorson, S., Carter, M., O’Connor, D., Murdoch, D., Kelly, D., Levin, M., & Pollard, A. (2026). Genome-wide association study of susceptibility to pneumococcal carriage amongst children. *medRxiv*. https://www.semanticscholar.org/paper/1f18313a40a39b5a4288b06c8abc8a2b2888a7a3

[14] He, Y., de Witte, L. D., Schubart, C., van Gastel, W., Koeleman, B., de Jong, S., Ophoff, R., Hol, E., & Boks, M. (2019). Liprin alfa 2 gene expression is increased by cannabis use and associated with neuropsychological function. *European Neuropsychopharmacology*. https://www.semanticscholar.org/paper/5867a963bc142500c1b47f42a415c2e0a8c3a870

[15] Fu, F., Niu, R., Zheng, M., Yang, X., Fan, L., Fu, W., & Zhang, S. (2023). Clinicopathological Significances and Prognostic Value of PPFIA4 in Colorectal Cancer. *Journal of Cancer*. https://www.semanticscholar.org/paper/8b6a82bb7f1ddd3dba2145f44767fa2233ea169f

[16] Katoh, M., & Katoh, M. (2003). Identification and characterization of human PPFIA4 gene in silico. *International Journal of Molecular Medicine*. https://www.semanticscholar.org/paper/207e355bb1a049f473854ed20176560589a1940c

[17] Uehara, D. T., Hayashi, S., Okamoto, N., Mizuno, S., Chinen, Y., Kosaki, R., Kosho, T., Kurosawa, K., Matsumoto, H., Mitsubuchi, H., Numabe, H., Saitoh, S., Makita, Y., Hata, A., Imoto, I., & Inazawa, J. (2016). SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements. *Journal of Human Genetics*. https://www.semanticscholar.org/paper/059ea32f9db33bf0bc7347ddc1f95f59749156bd

[18] Fu, F. (N/A). Clinicopathological significances and prognostic value of PPFIA4 in colorectal cancer. *Scientific Publication*. https://www.semanticscholar.org/paper/62c2ae2e9a39e71d0a7bb0fb38e32f3e8d2916ee

[19] Paiva, J. T., Peixoto, M., Bruneli, F., Alvarenga, A., Oliveira, H. R., Silva, A. A., Silva, D. A., Veroneze, R., Silva, F. F., & Lopes, P. S. (2020). Genetic parameters, genome-wide association and gene networks for milk and reproductive traits in Guzerá cattle. *Livestock Science*. https://www.semanticscholar.org/paper/e2cb8d5045e979c7261adfce5f9cb9f5cf57238a

[20] Beck, S. V., Kess, T., Nugent, C., Dempson, B., Chaput, G., Duffy, S., Smith, N., Bentzen, P., Pritchard, V., & Bradbury, I. (2026). A large-effect locus underlies migration timing in North American Atlantic salmon (Salmo salar). *Scientific Reports*. https://www.semanticscholar.org/paper/3178e6caa95e8d466c0bfc8e3c3b23d87e85b4b3

[21] Østergaard, M., Barbagallo, P., Frederiksen, H. R., Chung, W. K., Møller, R., Larsen, M. R., Freude, K. K., Verhage, M., & Sørensen, J. B. (2025). SNAP25 variant I67N: synaptic phenotypes, drug response and proteome changes in human neurons. *Brain : a journal of neurology*. https://www.semanticscholar.org/paper/4dad7addbb56866a0f386c83d5136c23c6a2c56b

[22] Beck, S. V., Kess, T., Nugent, C., Dempson, J., Chaput, G., Arno, H. E., Duffy, S., Smith, N., Bentzen, P., Kent, M., Pritchard, V., & Bradbury, I. (2025). Genomic Basis and Climate Change Vulnerability of Migration Timing in Atlantic Salmon (Salmo salar). *Evolutionary Applications*. https://www.semanticscholar.org/paper/e799864f516df7caf523158d342992b71e9f60c6

[23] Недашковский, И. С., Контэ, А. Ф., Сермягин, А. А., Кольцов, Д. Н., Волкова, В. В., Nedashkovsky, I. S., Konte, A., Sermyagin, A., Koltsov, D., & Volkova, V. (2026). Identification of candidate genes associated with conformation in Holsteinized Black and White cattle based on GWAS analysis. *Agricultural science Euro-North-East*. https://www.semanticscholar.org/paper/4e5a5b7fefdb0589800560dce0b9bd2571a3c0e1

[24] Feenstra, J. D. M., Rumi, E., Pietra, D., Schönegger, A., Bock, C., Cazzola, M., & Kralovics, R. (2015). Whole Exome Sequencing Reveals Clonal Evolution of Myeloproliferative Neoplasms to Acute Myeloid Leukemia. *Scientific Publication*. https://www.semanticscholar.org/paper/ded9097f7b8a2602adcaca9f1ca8f9f66283129d