Alternative titles; symbols
HGNC Approved Gene Symbol: PDX1
SNOMEDCT: 609571007;
Cytogenetic location: 13q12.2 Genomic coordinates (GRCh38) : 13:27,920,000-27,926,313 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.2 | {Diabetes mellitus, type II, susceptibility to} | 125853 | Autosomal dominant | 3 |
| MODY, type IV | 606392 | 3 | ||
| Pancreatic agenesis 1 | 260370 | Autosomal recessive | 3 |
PDX1 is a transactivator that binds the TAAT element in the promoter region of target genes, notably those involved in pancreas development (summary by Schwitzgebel et al. (2003)).
Endocrine pancreas consists primarily of 3 cell types, which are distinguished by their selective expression of insulin, glucagon, or somatostatin (Stoffel et al., 1995). In adult mammals, the insulin gene is expressed only in the beta-cell of the pancreatic islet, and its cell-specific transcription is determined by protein factors that bind to specific sites in the 5-prime-flanking region of the gene. Transcriptional control is mediated in part by 2 conserved mutationally sensitive AT-rich elements that are located between nucleotides -214 to -211 and -82 to -78. The major islet-specific protein, PDX1, that binds to these elements and activates insulin transcription, as well as the somatostatin gene, was cloned by Ohlsson et al. (1993) and termed insulin promoter factor-1 (IPF1) and by Leonard et al. (1993) and Miller et al. (1994), who termed it somatostatin transcription factor-1 (STF1/IDX1). PDX1 appears to be not only a key regulator of islet peptide hormone expression but also responsible for the development of the pancreas, most probably by determining maturation and differentiation of common pancreatic precursor cells in the developing gut.
Ohlsson et al. (1993) cloned mouse Pdx1 from an insulinoma cell line. The deduced 284-amino acid protein has a central homeodomain and a calculated molecular mass of 31 kD. Northern blot analysis of several mouse tissues and cells lines detected Pdx1 only in the mouse insulinoma cell line and in insulin-producing cell lines from other species. Immunohistochemical analysis of adult mouse pancreas localized Pdx1 within islets in a pattern typical for insulin-producing cells. In developing mouse embryos, Pdx1 expression was detected only in pancreatic anlagen or in the pancreas itself.
Schwitzgebel et al. (2003) reported that the deduced 283-amino acid human PDX1 protein has a calculated molecular mass of 46 kD. It has an N-terminal transactivation domain, followed by a pentapeptide motif for interaction with PBX1 (176310), and a homeodomain with 3 helices and a nuclear localization signal.
Schwitzgebel et al. (2003) reported that the PDX1 gene comprises 2 exons and spans 852 basepairs.
Stoffel et al. (1995) determined that the PDX1 gene is located on chromosome 13 by analysis of the pattern of segregation in human/rodent somatic cell hybrids. This assignment was determined independently and refined by fluorescence in situ hybridization to chromosome 13q12.1. Fiedorek and Kay (1995) mapped the mouse Pdx1 gene to the distal end of mouse chromosome 5 using interspecific backcross mapping.
The homeobox protein STF1 (PDX1, IDX1, IPF1) appears to serve as a master control switch for expression of both the exocrine and endocrine pancreatic developmental programs, as revealed by gene disruption studies in which targeted deletion of the gene leads to a 'null pancreas phenotype.' First detected in dorsal endoderm cells at embryonic day 8.5 of the mouse, STF1 is initially expressed in both exocrine and endocrine cells. As pancreatic morphogenesis proceeds, STF1 production is eventually restricted to beta and delta cells of the islets, where it appears to regulate expression of the insulin and somatostatin genes, respectively. Sharma et al. (1997) characterized a composite enhancer that directs STF1 expression to pancreatic islet cells via 2 functional elements that recognize the nuclear factors HNF-3-beta (FOXA2; 600288) and beta-2. Their results suggested that the expansion of pancreatic islet precursor cells during development may be restricted by hormonal cues that regulate STF1 gene expression.
Watada et al. (1996) showed that PDX1 can activate the promoter of the human IAPP gene (147940) and that this activation is mediated by at least 2 of the A element-like regions in the 5-prime flanking sequence.
Hart et al. (2000) showed that IPF1/PDX1 is required for the expression of the FGFR1 (136350) signaling component in beta cells, indicating that IPF1/PDX1 acts upstream of FGFR1 signaling in beta cells to maintain proper glucose sensing, insulin processing, and glucose homeostasis.
Using immunoprecipitation and transcriptional analysis, Liu et al. (2004) showed that mouse Pcif1 (SPOP; 602650) physically interacted with Pdx1 and downregulated the ability of Pdx1 to activate its target genes. The C terminus of Pdx1 mediated the functional interaction between Pcif1 and Pdx1.
Johnson et al. (2006) found that physiologic concentrations of insulin prevented serum withdrawal-induced apoptosis in isolated mouse and human islets. Insulin treatment was associated with the nuclear localization of Pdx1, and the prosurvival effects of insulin were largely absent in mouse islets 50% deficient in Pdx1. Proteomic analysis of insulin-treated human islets revealed increased expression of PSMD9 (603146), a PDX1-binding partner and regulator of beta-cell survival.
Gao et al. (2008) found that the winged helix transcription factors Foxa1 (602294) and Foxa2 co-occupied multiple regulatory domains in the mouse Pdx1 gene. Compound conditional ablation of both Foxa1 and Foxa2 in mouse pancreatic primordium resulted in complete loss of Pdx1 expression, severe pancreatic hypoplasia, disrupted acinar and islet development, hyperglycemia, and death shortly after birth. Foxa1 and Foxa2 predominantly occupied a distal enhancer over 6 kb upstream of the transcriptional start site in the Pdx1 gene, and their occupation of the proximal Pdx1 enhancer was developmentally regulated. Gao et al. (2008) concluded that regulation of PDX1 by FOXA1 and FOXA2 is a key early event controlling expansion and differentiation of the pancreatic primordia.
Mutations in PDX1 may be involved in several disorders, including agenesis of the pancreas or congenital pancreatic hypoplasia (PAGEN1; 260370) and diabetes mellitus (e.g., 222100, 125850). Altered regulation of insulin gene expression may contribute to the beta-cell dysfunction that characterizes diabetes mellitus. Other genes encoding proteins involved in the regulation of insulin gene expression have also been mapped: LMX1 (600298) to 1q22; CDX3 (600297) to 13q12.3; and ISL1 (600366) to 5q. These genes can be considered candidates for contributing to diabetes susceptibility in families showing linkage of diabetes mellitus with these regions.
Stoffers et al. (1997) identified a single-nucleotide deletion within codon 63 of the human IPF1 gene in a patient with pancreatic agenesis (600733.0001). The patient was homozygous for the point deletion, whereas both parents were heterozygous for the mutation. The deletion was not found in 184 chromosomes from normal individuals, indicating that the mutation was probably not a rare polymorphism. The point deletion caused a frameshift at the C-terminal border of the transactivation domain of IPF1, resulting in the translation of 59 novel codons before termination, amino proximal to the homeodomain essential for DNA binding. Expression of mutant IPF1 in COS-1 cells confirmed the expression of a prematurely terminated truncated protein of 16 kD. Thus, Stoffers et al. (1997) determined that the affected patient should have no functional IPF1 protein. They concluded that IPF1 appears to be a critical regulator of pancreatic development in humans as well as mice (Jonsson et al., 1994).
Stoffers et al. (1997) presented evidence suggesting that whereas the infant they reported previously with pancreatic agenesis was homozygous for the mutation that they referred as pro63fsdelC (600733.0001), heterozygotes in the pedigree had maturity-onset diabetes of the young, which they referred to as MODY4 (606392). The pedigree showed diabetes in 6 generations. The average age at onset was 35 years (range, 17 to 67 years). Six of 8 affected heterozygotes were treated with diet or oral hypoglycemic agents. None showed ketosis or other indications of severe insulin deficiency. Linkage to the MODY1 (125850), MODY2 (125851), and MODY3 (600496) loci was excluded by negative lod scores.
Macfarlane et al. (1999) and Hani et al. (1999) identified mutations in the IPF1 gene in association with type 2 diabetes. Studying Caucasian diabetic and nondiabetic subjects from the United Kingdom, Macfarlane et al. (1999) identified 3 novel IPF1 missense mutations (C18R, 600733.0005; D76N, 600733.0002; and R197H, 600733.0006) in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line. These mutations were found in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25 to 53 years of age. The authors concluded that mutations in the IPF1 gene may dispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the 'severity' of the specific mutation.
Hani et al. (1999) investigated 192 French families segrgating non-MODY type 2 diabetes and identified 3 novel IPF1 mutations, including 2 substitutions (Q59L, 600733.0003, and D76N) and an in-frame proline insertion (insCCG243, 600733.0004). Functional transactivation assays of these IPF1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF1 expression plasmids demonstrated a significant inhibition of basal insulin promoter activity (stronger with the insCCG243 mutant). They found that the insCCG243 mutation was linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion became progressively impaired. The lower-penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin secretion in nondiabetic subjects. They proposed that IPF1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes.
Using SSCP and heteroduplex analysis, Hansen et al. (2000) examined 200 Danish patients with late-onset type 2 diabetes and 44 Danish and Italian MODY patients for mutations in the IPF1 gene. In the patients with late-onset type 2 diabetes, they identified a noncoding G insertion/deletion polymorphism at nucleotide -108, a silent gly54-to-gly substitution, and the rare D76N variant. Moreover, a Danish MODY patient carried an ala140-to-thr (A140T) variant. Neither the D76N nor the A140T variant segregated with diabetes, and their transcriptional activation of the human insulin promoter expressed in vitro was indistinguishable from that of wildtype. The authors concluded that variants in the IPF1 gene are not a common cause of MODY or late-onset type 2 diabetes in the Caucasian population, and that in terms of insulin transcription, both the N76 and the T140 mutations are likely to represent functionally normal IPF1 variants with no direct role in the pathogenesis of MODY or late-onset type 2 diabetes mellitus.
Johansson and Grapin-Botton (2002) reviewed the tissue interactions, signaling pathways, and intracellular targets involved in the emergence of the pancreas primordium and its proliferation, morphogenesis, and differentiation. They pointed out that several genes of developmental relevance have an adult function as well and are implicated in disorders of the pancreas. The PDX1 gene functions during development in connection with pancreas bud expansion as well as beta-cell differentiation. In the adult, PDX1 functions as a transcriptional activator of the insulin and somatostatin genes. Mutations in the PDX1 gene can cause pancreatic agenesis, maturity-onset diabetes of the young, and possibly type 2 diabetes (600733.0002).
Schwitzgebel et al. (2003) reported compound heterozygous missense mutations in the IPF1/PDX1 gene (600733.0008, 600733.0009) leading to pancreatic agenesis (260370). Levels of IPF1 were severely decreased, and the authors proposed that a threshold for IPF1 expression during development was not achieved, resulting in pancreatic agenesis.
Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene previously identified by Stoffers et al. (1997) (600733.0001) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related.
In a boy and girl, first cousins born of consanguineous parents, who had permanent neonatal diabetes mellitus with subclinical exocrine deficiency mapping to chromosome 13q21, Nicolino et al. (2010) sequenced the candidate gene PDX1 and identified homozygosity for a missense mutation (E178G; 600733.0010). The girl had partial agenesis of the pancreas, with only the head visualized on ultrasound, whereas the boy appeared to have a normal-sized pancreas by ultrasound. The 4 parents, who were all heterozygous for E178G, were asymptomatic and nondiabetic, but showed abnormalities in insulin secretory responses during glucose tolerance testing.
Reclassified Variants
The D76N mutation (600733.0002) in the PDX1 gene that was identified in patients with type 2 diabetes (125853) by Macfarlane et al. (1999) has been reclassified as a variant of unknown significance.
The E224K mutation (600733.0007) in the PDX1 gene that was identified in patients with maturity-onset diabetes of the young type 4 (606392) by Cockburn et al. (2004) has been reclassified as a variant of unknown significance.
Jonsson et al. (1994) reported that targeted disruption of the Ipf1 gene encoding IPF1 in transgenic mice results in a failure of the pancreas to develop (pancreatic agenesis).
In vitro studies have shown that PBX1 regulates the activity of IPF1, a Para-Hox homeodomain transcription factor required for the development and function of the pancreas in mice and humans. To investigate in vivo roles of PBX1 in pancreatic development and function, Kim et al. (2002) examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation, and function in mice deficient for Pbx1. Pbx1 -/- embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day 15 or 16. In these embryos, expression of Isl1 and Atoh5 (604882), essential regulators of pancreatic morphogenesis and differentiation, was severely reduced. Pbx1 +/- adults had pancreatic islet malformations, impaired glucose tolerance, and hypoinsulinemia. Thus, Kim et al. (2002) concluded that PBX1 is essential for normal pancreatic development and function. Analysis of trans-heterozygous Pbx1 +/- and Ipf1 +/- mice revealed in vivo genetic interactions between Pbx1 and Ipf1 that are essential for postnatal pancreatic function. Trans-heterozygous mice developed age-dependent overt diabetes mellitus, unlike Pbx1 +/- or Ipf1 +/- mice. Mutations affecting the Ipf1 protein promote diabetes mellitus in mice and humans. Kim et al. (2002) concluded that perturbation of PBX1 activity may also promote susceptibility to diabetes mellitus.
Zhou et al. (2008) used a strategy of reexpressing key developmental regulators in vivo to identify a specific combination of 3 transcription factors, Neurog3 (604882), Pdx1, and Mafa (610303), that reprogrammed differentiated pancreatic exocrine cells in adult mice into cells that closely resembled beta cells. Induced beta cells were indistinguishable from endogenous islet beta cells in size, shape, and ultrastructure. They expressed genes essential for beta cell function and could ameliorate hyperglycemia by remodeling local vasculature and secreting insulin. Zhou et al. (2008) concluded that their study provided an example of cellular reprogramming using defined factors in an adult organ and suggested a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.
Using mice expressing a C-terminal truncated form of Pdx1, called Pdx1-delta C, Oliver-Krasinski et al. (2009) showed that the C-terminal domain was required to maintain all endocrine lineages in the pancreas, with beta and alpha cells being more sensitive to the C-terminal domain. Expression of a single Pdx1-delta C allele resulted in mild hyperglycemia at birth that progressed to marked hyperglycemia, then overt diabetes. Pdx1-delta C caused reduced expression of the proendocrine transcription factor Ngn3 (604882). Wildtype Pdx1 interacted with Hnf6 (ONECUT1; 604164), and the Pdx1/Hnf6 dimer activated a conserved enhancer region of Ngn3 directly. Homozygous Pdx1-delta C expression also reduced mRNA levels of Hnf6, Sox9 (608160), Foxa2 (600288), and Hnf1b (189907), all of which regulate Ngn3 expression. Oliver-Krasinski et al. (2009) concluded that PDX1 contributes to the specification of pancreatic endocrine progenitors by participating in the HNF6, SOX9, HNF1B, and FOXA2 transcription factor crossregulatory network and by directly regulating NGN3 expression.
Stoffers et al. (1997) found a frameshift resulting from a 1-bp deletion in the IPF1 gene in a female Caucasian infant in whom the diagnosis of pancreatic agenesis (PAGEN1; 260370) was made shortly after birth (Wright et al., 1993). The infant was underweight for gestational age and presented with neonatal diabetes mellitus at birth and, at age 18 days, with pancreatic exocrine insufficiency. Ultrasound examination revealed that the pancreas was absent. After replacement of insulin and pancreatic enzymes, she developed normally and at 5 years of age continued to do well. There was a strong family history of noninsulin-dependent diabetes mellitus. Stoffers et al. (1997) found the child to be homozygous for deletion of a single cytosine in codon 63 of the IPF1 gene, resulting in termination after 59 additional codons (Pro63fsdelC).
In a later paper, Stoffers et al. (1997) demonstrated that whereas homozygosity of the Pro63fsdelC mutation led to pancreatic agenesis, heterozygosity was associated with a new type of early-onset type 2 diabetes mellitus (MODY4; 606392).
In the course of expressing the mutant IPF1 protein in eukaryotic cells, Stoffers et al. (1998) detected a second IPF1 isoform, recognized by COOH- but not NH2-terminal-specific antisera. This isoform localized to the nucleus and retained DNA-binding functions. Internal translation initiating at an out-of-frame AUG accounted for the appearance of the protein. The reading frame crossed over to the wildtype IPF1 reading frame at the site of the point deletion just carboxy-proximal to the transactivation domain. Thus, the single mutated allele results in the translation of 2 IPF1 isoforms; the first consists of the NH2-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the COOH-terminal DNA-binding domain but lacks the transactivation domain. The COOH-terminal domain IPF1 isoform does not activate transcription and inhibits the transactivation functions of wildtype IPF1. This circumstance suggested that the mechanism of diabetes in individuals with this mutation may be not only reduced gene dosage but also a dominant-negative inhibition of transcription of the insulin gene and other beta cell-specific genes regulated by the mutant IPF1.
Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene (188delC; Pro63fsTer60) identified by Stoffers et al. (1997) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related.
Fajans et al. (2010) restudied the family reported by Thomas et al. (2009), ultimately identifying 110 members of the 5-generation Michigan-Kentucky pedigree; 34 family members were being treated for diabetes, and 10 of those diabetics carried the 1-bp deletion in PDX1 (188delC) and were considered to have MODY4. Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by the Michigan-Kentucky pedigree and the Virginia pedigree, originally reported by Wright et al. (1993), that also carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands and that a complex pedigree structure connected the 2 probands.
This variant, formerly titled TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database (v4.0) by Hamosh (2024).
In a study of diabetics in the United Kingdom, Macfarlane et al. (1999) identified an asp76-to-asn (D76N) mutation in patients with type 2 diabetes (125853). This and 2 other missense mutations (C18R, 600733.0005 and R197H, 600733.0006) were present in 1% of the population and predisposed subjects to type 2 diabetes with a relative risk of 3.0. They appeared not to be highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25 to 53 years of age. Hani et al. (1999) likewise found a low penetrance D76N mutation in the course of studying 192 French families segregating non-MODY type 2 diabetes. They found that this and a gln59-to-leu missense mutation (Q59L; 600733.0003) carried a relative risk of 12.6 for type 2 diabetes and showed decreased glucose-stimulated insulin-secretion in nondiabetic subjects.
Hamosh (2024) noted that the D76N mutation was present in 7,550 of 1,545,430 alleles and in 26 homozygotes, with an allele frequency of 0.004885, in the gnomAD database (v4.0).
Hani et al. (1999) investigated 192 French families segregating non-MODY type 2 diabetes (T2D; 125853) and identified 3 novel IPF1 mutations, including 2 substitutions (Q59L and D76N, 600733.0002) and an in-frame proline insertion (insCCG243, 600733.0004). Functional transactivation assays of these IPF1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF1 expression plasmids demonstrated a significant inhibition of basal insulin promoter activity (stronger with the insCCG243 mutant). They found that the insCCG243 mutation was linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion became progressively impaired. The lower-penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin secretion in nondiabetic subjects. They proposed that IPF1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes.
Hani et al. (1999) investigated 192 French families segregating non-MODY type 2 diabetes (T2D; 125853) and identified 3 novel IPF1 mutations, including 2 substitutions (Q59L, 600733.0003 and D76N, 600733.0002) and an in-frame proline insertion, insCCG243. Functional transactivation assays of these IPF1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF1 expression plasmids demonstrated a significant inhibition of basal insulin promoter activity (stronger with the insCCG243 mutant). They found that the insCCG243 mutation was linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion became progressively impaired. The lower-penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin secretion in nondiabetic subjects. They proposed that IPF1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes.
Studying Caucasian diabetic and nondiabetic subjects from the United Kingdom, Macfarlane et al. (1999) identified 3 novel IPF1 missense mutations (C18R; D76N, 600733.0002; and R197H, 600733.0006) in patients with type 2 diabetes (T2D; 125853). Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line. These mutations were found in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25 to 53 years of age.
Studying Caucasian diabetic and nondiabetic subjects from the United Kingdom, Macfarlane et al. (1999) identified 3 novel IPF1 missense mutations (C18R, 600733.0005; D76N, 600733.0002; and R197H) in patients with type 2 diabetes (T2D; 125853). Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line. These mutations were found in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25 to 53 years of age.
This variant, formerly titled MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 4, has been reclassified based on the report of Lek et al. (2016).
In 2 Indo-Trinidadian families with type 2 diabetes diagnosed before 40 years of age, Cockburn et al. (2004) found a heterozygous G-to-A transition at nucleotide 670 in exon 2 of the IPF1 gene that resulted in a glu224-to-lys (E224K) amino acid substitution. The mutation was present on the same haplotype in both families, suggesting founder effect. The mutation cosegregated with early-onset diabetes or impaired glucose tolerance in the larger family, suggestive of the type 4 form of maturity-onset diabetes of the young (MODY4; 606392) rather than type 2 diabetes (125853). Functional studies of E224K showed reduced transactivation activity.
Lek et al. (2016) noted that the E224K variant has a high allele frequency (0.0128) in the South Asian population in the ExAC database, suggesting that it is not pathogenic.
In a female infant with pancreatic agenesis (PAGEN1; 260370), Schwitzgebel et al. (2003) identified compound heterozygosity for 2 missense mutations in exon 2 of the IPF1 gene: a 319G-T transversion resulting in a glu164-to-asp (E164D) substitution, and a 359G-A transition resulting in a glu178-to-lys (E178K; 600733.0009) substitution, both at highly conserved residues within helices 1 and 2, respectively, of the homeodomain. Her parents, who had high normal fasting glucose levels but no glucose intolerance, were each heterozygous for 1 of the mutations; a maternal uncle who had type 2 diabetes (T2D; 125853) was heterozygous for E164D. Both mutants decreased the protein half-life significantly, leading to intracellular IPF1 levels of 36% and 27% of wildtype levels. Both mutant proteins were translocated normally to the nucleus, and their DNA-binding activity on different known target promoters was similar to that of wildtype protein. However, transcriptional activity of both mutant IPF1 proteins, alone or in combination with FOXA2 (600288), PBX1 (176310), or the heterodimer E47-beta-2 (see 147141) was reduced, findings accounted for by decreased IPF1 steady-state levels and not by impaired protein-protein interactions. The authors concluded that IPF1 level is critical for human pancreas formation.
For discussion of the glu178-to-lys (E178K) mutation in the PDX1 gene that was found in compound heterozygous state in a patient with pancreatic agenesis (PAGEN1; 260370) by Schwitzgebel et al. (2003), see 600733.0008.
In a boy and girl, first cousins born of consanguineous parents, who had permanent neonatal diabetes mellitus with subclinical exocrine deficiency (PAGEN1; 260370), Nicolino et al. (2010) identified homozygosity for a 641A-G transition in the PDX1 gene, resulting in a glu178-to-gly (E178G) substitution at a residue within the highly conserved second helix of the homeodomain. Functional analysis demonstrated that mutant PDX1 had significantly reduced transactivation activity compared to wildtype, despite normal nuclear localization, expression level, and chromatin occupancy. The girl had partial agenesis of the pancreas (260370), with only the head visualized on ultrasound, whereas the boy appeared to have a normal-sized pancreas by ultrasound. The 4 parents, who were all heterozygous for E178G, were asymptomatic and nondiabetic, but showed abnormalities in insulin secretory responses during glucose tolerance testing. None of the obligate carriers in the pedigree was reported to be diabetic. The mutation was not found in 368 unrelated Caucasian controls.
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