Alternative titles; symbols
SNOMEDCT: 609571007; ORPHA: 552; DO: 0111103;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q12.2 | MODY, type IV | 606392 | 3 | PDX1 | 600733 |
A number sign (#) is used with this entry because of evidence that MODY type 4 (MODY4) is caused by heterozygous mutation in the IPF1 gene (PDX1; 600733) on chromosome 13q12.
For a phenotypic description and discussion of genetic heterogeneity of MODY, see 606391.
Mutation in the IPF1 (PDX1) gene is a rare cause of MODY (Fajans et al., 2001). In a consanguineous family, originally reported by Wright et al. (1993), in which an infant with pancreatic agenesis (260370) was homozygous for a 1-bp deletion in the PDX1 gene (600733.0001), Stoffers et al. (1997) found that members heterozygous for this mutation had early-onset type 2 diabetes mellitus, which they designated MODY4. The expression of diabetes in this family may occur at later ages than in families with other types of MODY.
In the course of expressing the mutant IPF1 protein (Stoffers et al., 1997) in eukaryotic cells, Stoffers et al. (1998) detected a second IPF1 isoform, recognized by C-terminal but not N-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 N-terminal transactivation domain and is sequestered in the cytoplasm, and the second contains the C-terminal DNA-binding domain but lacks the transactivation domain. The C-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 identified by Stoffers et al. (1997) (600733.0001) in a similar family. Thomas et al. (2009) suggested that the 2 families might be related.
Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by a Michigan-Kentucky pedigree originally reported by Thomas et al. (2009) and a Virginia pedigree, originally reported by Wright et al. (1993), both of which 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.
Reclassified Variants
The E224K mutation (600733.0007) in the IPF1 gene that was identified in patients with maturity-onset diabetes of the young type 4 by Cockburn et al. (2004) has been reclassified as a variant of unknown significance.
Cockburn, B. N., Bermano, G., Boodram, L.-L. G., Teelucksingh, S., Tsuchiya, T., Mahabir, D., Allan, A. B., Stein, R., Docherty, K., Bell, G. I. Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family. J. Clin. Endocr. Metab. 89: 971-978, 2004. [PubMed: 14764823] [Full Text: https://doi.org/10.1210/jc.2003-031282]
Fajans, S. S., Bell, G. I., Paz, V. P., Below, J. E., Cox, N. J., Martin, C., Thomas, I. H., Chen, M. Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Transl. Res. 156: 7-14, 2010. [PubMed: 20621032] [Full Text: https://doi.org/10.1016/j.trsl.2010.03.003]
Fajans, S. S., Bell, G. I., Polonsky, K. S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New Eng. J. Med. 345: 971-980, 2001. [PubMed: 11575290] [Full Text: https://doi.org/10.1056/NEJMra002168]
Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter) Nature Genet. 17: 138-141, 1997. [PubMed: 9326926] [Full Text: https://doi.org/10.1038/ng1097-138]
Stoffers, D. A., Stanojevic, V., Habener, J. F. Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. J. Clin. Invest. 102: 232-241, 1998. [PubMed: 9649577] [Full Text: https://doi.org/10.1172/JCI2242]
Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S. Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation. Pediat. Diabetes 10: 492-496, 2009. [PubMed: 19496967] [Full Text: https://doi.org/10.1111/j.1399-5448.2009.00526.x]
Wright, N. M., Metzger, D. L., Borowitz, S. M., Clarke, W. L. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. Am. J. Dis. Child. 147: 607-609, 1993. [PubMed: 8506821] [Full Text: https://doi.org/10.1001/archpedi.1993.02160300013005]