Alternative titles; symbols
HGNC Approved Gene Symbol: PAX4
SNOMEDCT: 44054006, 609576002; ICD10CM: E11;
Cytogenetic location: 7q32.1 Genomic coordinates (GRCh38): 7:127,610,292-127,618,142 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q32.1 | {Diabetes mellitus, ketosis-prone, susceptibility to} | 612227 | Autosomal dominant; Autosomal recessive | 3 |
| Diabetes mellitus, type 2 | 125853 | Autosomal dominant | 3 | |
| Maturity-onset diabetes of the young, type IX | 612225 | 3 |
Pax genes encode a family of transcription factors containing a paired box domain that are essentially required for the formation of several tissues from all germ layers in the mammalian embryo. Specifically, in organogenesis, they are involved in triggering early events of cell differentiation. The differentiation of endoderm-derived endocrine pancreas is mediated through PAX4 and PAX6 (607108) (Mansouri et al., 1999).
By searching sequence databases with a mouse Pax4 cDNA, Matsushita et al. (1998) and Inoue et al. (1998) identified a human cosmid clone that maps to chromosome 7q31.3 and contains the human PAX4 sequence. The human PAX4 gene encodes a deduced 350-amino acid protein that is 80% identical to the deduced mouse Pax4 protein. RT-PCR detected mouse Pax4 expression in pancreatic islets and islet beta cell lines, but not in the other 13 adult mouse organs examined (Matsushita et al., 1998).
Bonthron et al. (1998) described the partial structure of PAX4, including the entire coding region. They found that the gene has 10 exons, with the paired domain and homeodomain contained in 6 exons, which they named B to G.
Pilz et al. (1993) used mouse Pax4 cDNAs as probes to map the human homolog to chromosome 7 in somatic cell hybrids. By use of hybrids carrying translocated chromosomes, they showed that the human PAX4 gene is located on 7q22-qter. The mouse Pax4 gene is located on chromosome 6. By analysis of somatic cell hybrids, Stapleton et al. (1993) confirmed the assignment of the human PAX4 gene to chromosome 7. Tamura et al. (1994) localized the human PAX4 gene to 7q32 using FISH.
Sosa-Pineda et al. (1997) showed by study of knockout mice that the Pax4 gene is essential for differentiation of insulin-producing beta cells in mammalian pancreas. St-Onge et al. (1997) concluded that both PAX4 and PAX6 (607108) are required for endocrine fate in the pancreas.
Using different cell-specific promoters, Collombat et al. (2009) showed that overexpression of Pax4 in early mouse pancreatic cells induced their differentiation toward beta cells. Furthermore, overexpression of Pax4 in mature pancreatic alpha cells induced their respecification toward a beta-cell fate.
Brun et al. (2008) found that expression of PAX4 mRNA was increased in cultured human islets by mitogens, glucose, insulin, and GLP1 (GCG; 138030). However, unlike mouse beta cells, human beta cells did not replicate following PAX4 upregulation. PAX4 expression was also increased in islets derived from type 2 diabetic donors and correlated with hyperglycemia.
By Western blot analysis, Majumder et al. (2021) showed that levels of GRB2 (108355) and NOX4 (605261) were elevated in tissues from mouse models for Alzheimer disease (AD; see 104300) and type 2 diabetes (T2D; 125853), as well as in tissues from AD and T2D patients. Knockdown analysis in SHSY-5Y and HepG2 cells revealed that miRNA1271 targeted and restricted expression of ALK (105590) and RYK (600524), which elevated expression of GRB2 and NOX4. Moreover, PAX4, a transcription factor for both GRB2 and NOX4, was overexpressed during ALK and RYK knockdown due to reduced expression of the PAX4 suppressor ARX (300382) via beta-catenin (see 116806) signaling. In addition, expression of various cytoskeletal proteins was downregulated in liver tissue of T2D patients and in ALK/RYK knockdown cells, but overexpression of GRB2 reversed the cytoskeletal degradation through interaction with NOX4.
Diabetes Mellitus, Type 2
Shimajiri et al. (2001) scanned the PAX4 gene in 200 unrelated Japanese patients with type 2 diabetes (125853) and identified an arg121-to-tyr mutation (R121W; 167413.0002) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation, located in the paired domain, was not found in 161 nondiabetic subjects (p = 0.01); functional studies indicated that PAX4 transcriptional activity was impaired due to lack of DNA binding. In a second screening, conducted in 192 additional Japanese patients with type 2 diabetes, 12 heterozygotes but no homozygotes were identified (mutant allele frequency, 3.1%).
Ketosis-Prone Diabetes
Citing clinical similarities between the PAX4 mutation-positive Japanese patients with type 2 diabetes described by Shimajiri et al. (2001) and West African patients with ketosis-prone diabetes (KPD; 612227), Mauvais-Jarvis et al. (2004) screened 101 unrelated West African patients with KPD for mutations in the PAX4 gene and identified a variant (R133W; 167413.0002), specific to the population of West African ancestry, that predisposes to KPD under a recessive model. Homozygous R133W PAX4 mutations were found in 3 Senegalese men and 1 man from the Ivory Coast (4% of patients with KPD), but not in 355 controls or 147 individuals with common type 2 or type 1 diabetes. In addition, 1 Cameroonian man with KPD was heterozygous for a rare PAX4 variant (R37W; 167413.0003) that was not found in 255 controls of West African ancestry and that showed a more severe biochemical phenotype than R133W. The authors concluded that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggested that KPD, like maturity-onset diabetes of the young (MODY: see 606391), is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.
Maturity-onset Diabetes of the Young, Type 9
Plengvidhya et al. (2007) screened the PAX4 gene in 46 Thai probands with maturity-onset diabetes of the young (MODY9; 612225) who did not have mutations in known MODY genes and identified mutations in 2 probands (167413.0004 and 167413.0005). Neither mutation was found in 344 controls of Thai origin.
Collombat et al. (2003) found that the pancreatic phenotype of Arx (300382)-null embryos was opposite that of Pax4-null embryos. RT-PCR detected elevated Pax4 mRNA in Arx-null embryos and elevated Arx mRNA in Pax4-null embryos. Examination of protein expression in single islet cells revealed coexpression of Arx and Pax4 in wildtype endocrine progenitors. As development continued, one prevailed over the other to determine the fate of the endocrine cells. Collombat et al. (2003) concluded that Arx and Pax4 are required for proper apportionment of alpha-, beta-, and gamma-cell numbers in islets of Langerhans.
Shimajiri et al. (2001) scanned the PAX4 gene in 200 unrelated Japanese probands with type 2 diabetes mellitus (T2D; 125853) and identified a C-T transition in exon 3, resulting in an arg121-to-trp (R121W) substitution in the PAX4 paired domain, in 6 heterozygous probands and 1 homozygous proband (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects (p = 0.01). There was a family history of diabetes or impaired glucose tolerance in 6 of the 7 mutation-positive probands. Age at diagnosis ranged from 29 to 49 years, and 4 of 7 had transient insulin therapy at the onset. The homozygous proband was a 44-year-old woman who presented at age 29 years with weight loss, fatigue, polydipsia, and polyuria, and was found to be hyperglycemic but was negative for islet cell antibodies or urine ketone bodies; she required insulin therapy within a year after diagnosis. Her mother, who was heterozygous for the mutation, had impaired glucose tolerance; oral glucose tolerance tests in her clinically asymptomatic heterozygous father and sister as well as another heterozygous carrier, son of a mutation-positive diabetic mother, showed significantly lower insulin-to-glucose ratios than those of controls (p less than 0.001). In functional studies, the R121W mutation showed 92% less suppression of PAX6 (607108) than wildtype, and almost completely lacked binding activity. In a second screening of 192 Japanese patients with type 2 diabetes, 12 heterozygotes but no homozygotes were identified (mutant allele frequency, 3.1%).
Mauvais-Jarvis et al. (2004) screened 101 West African patients with ketosis-prone diabetes mellitus (KPD; 612227) for mutations in the PAX4 gene and identified a 397C-T transition resulting in an arg133-to-trp (R133W) substitution, specific to the population of West African ancestry, that predisposes to KPD under a recessive model. Homozygous R133W PAX4 carriers were found in 4% of KPD patients but not in 355 controls or 147 subjects with common type 2 (125853) or type 1 (222100) diabetes. Three of the 4 homozygous probands had a known family history of diabetes; all 4 were successfully treated with oral hypoglycemic agents after remission of an initial period of insulin dependence. In an alpha-TC1.6 cell line, transcriptional repression of target gene promoters by the R133W variant was only 37% of wildtype. A glucagon stimulation test revealed a more severe alteration in insulin secretory reserve in the 4 R133W homozygotes compared to other KPD patients.
Mauvais-Jarvis et al. (2004) screened the PAX4 gene in 101 West African patients with ketosis-prone diabetes mellitus (KPD; 612227) and identified a Cameroonian man, diagnosed with KPD at age 39, who was heterozygous for a 109C-T transition in the PAX4 gene, resulting in an arg37-to-trp (R37W) substitution, that was not found in 255 West African controls. In functional studies, repression of reporter activity and binding to DNA sequences by the R37W variant were only 45% and 50% compared to wildtype, respectively. The family history was positive for diabetes in the patient's father. The patient was continuously insulin-dependent from the time of diagnosis, indicating a severe beta-cell insulin secretory defect, and a glucagon stimulation test was consistent with total insulin deficiency.
In a 21-year-old Thai woman who was diagnosed with diabetes at age 20 (MODY9; 612225), Plengvidhya et al. (2007) identified heterozygosity for a C-to-T transition in exon 4 of the PAX4 gene, resulting in an arg164-to-trp (R164W) substitution. The mutation was also found in the proband's father and an older sister, who were diagnosed with type 2 diabetes at ages 50 years and 29 years, respectively, and in a younger brother who was diagnosed with impaired glucose tolerance at 13 years of age. Two sisters who had impaired glucose tolerance but did not carry the mutation were believed to be phenocopies. Functional studies showed that the R164W mutant repressed activity of the insulin and glucagon promoters by only 35% compared to 50% and 57%, respectively, with wildtype PAX4. The mutation was not found in 344 controls of Thai origin.
In a Thai woman with maturity-onset diabetes of the young (MODY9; 612225), Plengvidhya et al. (2007) identified heterozygosity for a -1G-A transition in intron 7 of the PAX4 gene, predicted to abolish the acceptor splice site of intron 7 and potentially cause exon skipping, intron retention, or usage of another acceptor splice site. She had 2 older sisters and an older brother with diabetes and early-onset renal failure, who all died at 52 to 53 years of age of end-stage renal disease. Her youngest sister was diagnosed with diabetes at 30 years of age and had diabetic retinopathy and nephropathy (see 603933) at age 40. Family members were unavailable for DNA analysis; the mutation was not found in 344 controls of Thai origin.
Bonthron, D. T., Dunlop, N., Barr, D. G. D., El Sanousi, A. A., Al-Gazali, L. I. Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome. J. Med. Genet. 35: 288-292, 1998. [PubMed: 9598721] [Full Text: https://doi.org/10.1136/jmg.35.4.288]
Brun, T., Hu He, K. H., Lupi, R., Boehm, B., Wojtusciszyn, A., Sauter, N., Donath, M., Marchetti, P., Maedler, K., Gauthier, B. R. The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1. Hum. Molec. Genet. 17: 478-489, 2008. [PubMed: 17989064] [Full Text: https://doi.org/10.1093/hmg/ddm325]
Collombat, P., Mansouri, A., Hecksher-Sorensen, J., Serup, P., Krull, J., Gradwohl, G., Gruss, P. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 17: 2591-2603, 2003. [PubMed: 14561778] [Full Text: https://doi.org/10.1101/gad.269003]
Collombat, P., Xu, X., Ravassard, P., Sosa-Pineda, B., Dussaud, S., Billestrup, N., Madsen, O. D., Serup, P., Heimberg, H., Mansouri, A. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138: 449-462, 2009. [PubMed: 19665969] [Full Text: https://doi.org/10.1016/j.cell.2009.05.035]
Inoue, H., Nomiyama, J., Nakai, K., Matsutani, A., Tanizawa, Y., Oka, Y. Isolation of full-length cDNA of mouse PAX4 gene and identification of its human homologue. Biochem. Biophys. Res. Commun. 243: 628-633, 1998. [PubMed: 9480859] [Full Text: https://doi.org/10.1006/bbrc.1998.8144]
Majumder, P., Chanda, K., Das, D., Singh, B. K., Chakrabarti, P., Jana, N. R., Mukhopadhyay, D. A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's disease and type 2 diabetes. Biochem. J. 478: 3297-3317, 2021. [PubMed: 34409981] [Full Text: https://doi.org/10.1042/BCJ20210175]
Mansouri, A., St-Onge, L., Gruss, P. Role of Pax genes in endoderm-derived organs. Trends Endocr. Metab. 10: 164-167, 1999. [PubMed: 10322412] [Full Text: https://doi.org/10.1016/s1043-2760(98)00133-7]
Matsushita, T., Yamaoka, T., Otsuka, S., Moritani, M., Matsumoto, T., Itakura, M. Molecular cloning of mouse paired-box-containing gene (Pax)-4 from an islet beta cell line and deduced sequence of human Pax-4. Biochem. Biophys. Res. Commun. 242: 176-180, 1998. [PubMed: 9439631] [Full Text: https://doi.org/10.1006/bbrc.1997.7935]
Mauvais-Jarvis, F., Smith, S. B., Le May, C., Leal, S. M., Gautier, J.-F., Molokhia, M., Riveline, J.-P., Rajan, A. S., Kevorkian, J.-P., Zhang, S., Vexiau, P., German, M. S., Vaisse, C. PAX4 gene variations predispose to ketosis-prone diabetes. Hum. Molec. Genet. 13: 3151-3159, 2004. [PubMed: 15509590] [Full Text: https://doi.org/10.1093/hmg/ddh341]
Pilz, A. J., Povey, S., Gruss, P., Abbott, C. M. Mapping of the human homologs of the murine paired-box-containing genes. Mammalian Genome 4: 78-82, 1993. [PubMed: 8431641] [Full Text: https://doi.org/10.1007/BF00290430]
Plengvidhya, N., Kooptiwut, S., Songtawee, N., Doi, A., Furuta, H., Nishi, M., Nanjo, K., Tantibhedhyangkul, W., Boonyasrisawat, W., Yenchitsomanus, P., Doria, A., Banchuin, N. PAX4 mutations in Thais with maturity onset diabetes of the young. J. Clin. Endocr. Metab. 92: 2821-2826, 2007. [PubMed: 17426099] [Full Text: https://doi.org/10.1210/jc.2006-1927]
Shimajiri, Y., Sanke, T., Furuta, H., Hanabusa, T., Nakagawa, T., Fujitani, Y., Kajimoto, Y., Takasu, N., Nanjo, K. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes 50: 2864-2869, 2001. [PubMed: 11723072] [Full Text: https://doi.org/10.2337/diabetes.50.12.2864]
Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G., Gruss, P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 386: 399-402, 1997. [PubMed: 9121556] [Full Text: https://doi.org/10.1038/386399a0]
St-Onge, L., Sosa-Pineda, B., Chowdhury, K., Mansouri, A., Gruss, P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 387: 406-409, 1997. [PubMed: 9163426] [Full Text: https://doi.org/10.1038/387406a0]
Stapleton, P., Weith, A., Urbanek, P., Kozmik, Z., Busslinger, M. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nature Genet. 3: 292-298, 1993. [PubMed: 7981748] [Full Text: https://doi.org/10.1038/ng0493-292]
Tamura, T., Izumikawa, Y., Kishino, T., Soejima, H., Jinno, Y., Niikawa, N. Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 66: 132-134, 1994. [PubMed: 8287686] [Full Text: https://doi.org/10.1159/000133684]