PDX1
protein-codingpancreatic and duodenal homeobox 1, the group of HOXL subclass homeoboxes
Gene summary
The protein encoded by this gene is a transcriptional activator of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide, and glucose transporter type 2. The encoded nuclear protein is involved in the early development of the pancreas and plays a major role in glucose-dependent regulation of insulin gene expression. Defects in this gene are a cause of pancreatic agenesis, which can lead to early-onset insulin-dependent diabetes mellitus (IDDM), as well as maturity onset diabetes of the young type 4 (MODY4). [provided by RefSeq, Aug 2017]
- IPF1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011667
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011667
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
PDX1: Monogenic diabetes, autosomal dominant (MONDO: 0015967) Moderate *PDX1* was first reported in relation to autosomal dominant monogenic diabetes in 1997 (Stoffers et al., 1997). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Variants in this gene have been reported in at least 13 probands in 9 publications. These include three probands heterozygous for the c.188del/p.Pro63fs variant (PMIDs: 9326926, 28436541, 31595705), which was shown to create two isoforms, one which is transcriptionally inactive and one which localizes to the nucleus and binds DNA but lacks a transactivation domain and thus behaves as a null or possibly dominant negative variant (PMID: 9649577). Homozygosity for c.188del/p.Pro63fs causes pancreatic agenesis and neonatal diabetes in the homozygous state (PMIDs: 8988180, 19496967). The other probands had missense variants (PMIDs: 10720084, 10545530, 31595705, 33746035, 26226118, 25041077, 31333579), of which five were too common in gnomAD to cause monogenic diabetes (PMIDs 10720084, 10545530, 26226118, 31333579). Summary of case-level data: 5.2 points. Notably, heterozygous parents of individuals with pancreatic agenesis with neonatal diabetes due to homozygosity or compound heterozygosity for a *PDX1* missense variant do not consistently have diabetes (PMIDs: 12970316, 200009086), and thus the role of missense *PDX1* variants in autosomal dominant monogenic diabetes is unclear. The c.188del/p.Pro63fs variant segregated with diabetes in 10 meioses in 1 family (LOD = 3.43, 1 point). Total score for genetic evidence: 6.2 points. Evidence from 2 mouse models has supported the role of PDX1 disruption in impaired glucose-stimulated insulin secretion and impaired glucose tolerance (PMIDs: 11781323, 9637677). An in vitro functional assay supported the role of PDX1 disruption in impaired proinsulin processing and insulin secretion (PMID: 15756539). *PDX1* expression has been confirmed in the pancreas vis eQTL analysis (PMID: 23715323). Summary of experimental data: 5 points. Total score for genetic evidence and experimental evidence: 11.2 points. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, monogenic diabetes (OMIM:606391) and pancreatic agenesis with neonatal diabetes (OMIM:260370). The split curation for pancreatic agenesis with neonatal diabetes mellitus has been curated separately. In summary, there is moderate evidence to support the relationship between *PDX1* and autosomal dominant monogenic diabetes, in particular the c.188del/p.Pro63fs variant which creates two functionally inactive isoforms. Missense variants should be interpreted with caution.
Inheritance Pattern: AR
Disease ID:MONDO:0024547
Submitter: ClinGen
*PDX1* was first reported in relation to autosomal recessive pancreatic agenesis with neonatal diabetes mellitus in 1997 (Stoffers et al., PMID: 8988180). Five variants (missense and frameshift) that have been reported in 4 probands in 4 publications (PMIDs: 8988180, 12970316, 19496967, 20009086) are included in this curation. The mechanism of pathogenicity appears to be LOF through a variety of mechanisms. One variant, c.188del/p.Pro63fs, reported in the homozygous state in at least two patients with neonatal diabetes and pancreatic agenesis (PMIDs: 8988180, 19496967), was shown to create two isoforms, one which is transcriptionally inactive and one which localizes to the nucleus and binds DNA but lacks a transactivation domain (PMID: 9649577). Two missense variants reported in the compound heterozygous state in a patient with diabetes and pancreatic agenesis were shown to reduce levels of the IPF-1 protein encoded by *PDX1* (PMID: 12970316). Two cousins with neonatal diabetes without pancreatic agenesis but found to have subclinical evidence of exocrine pancreatic deficiency were homozygous for a missense variant found to reduce *PDX1* transactivation (PMID: 20009086). Overall case-level evidence: 8 points. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 15756539, 23715323, 7935793, 8631275). An in vitro functional assay supported the role of *PDX1* disruption in impaired proinsulin processing and insulin secretion (PMID: 15756539). *PDX1* expression has been confirmed in the pancreas via eQTL analysis (PMID: 23715323). Evidence from 2 mouse models has supported the role of *PDX1* disruption in pancreatic agenesis (PMIDs: 7935793, 8631275). Overall experimental evidence 5 points. Overall genetic and experimental evidence 13 points. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, autosomal dominant monogenic diabetes (OMIM:606391) and autosomal recessive pancreatic agenesis 1 with neonatal diabetes (OMIM: 260370). The split curation for autosomal dominant monogenic diabetes has been curated separately. In summary, *PDX1* is definitively associated with autosomal recessive pancreatic agenesis or pancreatic exocrine dysfunction with neonatal diabetes mellitus, particularly through the c.188del variant, which effectively leads to complete loss of function in homozygotes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0100164
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0024547
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011667
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0024547
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0100164
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0024547
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0024547
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011667
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009832
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Endocrine; Gastrointestinal; Neurologic
Intervention: Endocrine; Gastrointestinal
Rationale: Individuals may manifest in infancy with findings including intrauterine growth retardation, postnatal growth deficiency, and signs of diabetes mellitus (eg, hyperglycemia, glycosuria), as well as severe dehydration, and recognition can allow preventive measures related to potential sequelae, surveillance (eg, with blood glucose monitoring as well as surveillance for other common sequelae of diabetes mellitus affecting systems such as the renal and ophthalmogic systems); In the case of an acute diabetic crisis, rapid treatment (eg, with rehydration and IV insulin, transitioning to SQ insulin when stable) is indicated, though rapid-acting and (non-continuous) short-acting insulin preparations may result in severe hypoglycemia in young patients; Due to exocrine (as well as endocrine) pancreatic insufficiency, some individuals may benefit from enzymatic replacement
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PDX1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000209.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 64 | 1 | 70 | ||
| missense | 2 | 7 | 132 | 8 | 2 | 151 |
| nonsense | 1 | 7 | 8 | |||
| start loss | 0 | |||||
| frameshift | 2 | 7 | 12 | 21 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 4 | 16 | 156 | 72 | 3 | 251 |
Highest pathogenic variant AF is 0.000010377252
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000200.1 | 2 | MANE Select | |
| Ensembl | ENSP00000370421.4 | 2 | MANE Select | |
| Ensembl | ENSP00000811192.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pdx1 | Danio rerio | Structure: acinar cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Type II diabetes mellitus - Homo sapiens (human)
- Maturity onset diabetes of the young - Homo sapiens (human)
- Insulin secretion - Homo sapiens (human)
- Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
- Type II diabetes mellitus
Biological Process
- negative regulation of transcription by RNA polymerase II
- liver development
- type B pancreatic cell differentiation
- glucose metabolic process
- generation of precursor metabolites and energy
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- chromatin binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- nuclear speck
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000381033
- Coding exons
- 2
- Length
- 6212
- Individuals with no LoFs
- 125549
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125557
- p
- 0.0000319
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.266 | 167 | 158 | 1.06 | 0.00000714 | 1757 |
| Missense (PolyPhen) | 41 | 49.592 | 0.82674 | 561 | ||
| Synonymous | -2.81 | 106 | 75.0 | 1.41 | 0.00000360 | 615 |
| Loss of Function | 1.47 | 4 | 8.69 | 0.460 | 3.71e-7 | 95 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000072 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000055 | 0.000053 | rare |
| South Asian | 0.000034 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription. As part of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element. Binds preferentially the DNA motif 5'-[CT]TAAT[TG]-3'. During development, specifies the early pancreatic epithelium, permitting its proliferation, branching and subsequent differentiation. At adult stage, required for maintaining the hormone-producing phenotype of the beta-cell.;
- Disease
- DISEASE: Pancreatic agenesis 1 (PAGEN1) [MIM:260370]: A disease characterized by isolated hypoplasia or agenesis of the pancreas, pancreatic beta-cell failure resulting in neonatal insulin- dependent diabetes mellitus, and exocrine pancreatic insufficiency. {ECO:0000269|PubMed:8988180}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Maturity-onset diabetes of the young 4 (MODY4) [MIM:606392]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:9326926}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.603
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.683
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |