Alternative titles; symbols
SNOMEDCT: 609575003; ORPHA: 552; DO: 0111105;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.13 | Maturity-onset diabetes of the young, type VIII | 609812 | Autosomal dominant | 3 | CEL | 114840 |
A number sign (#) is used with this entry because maturity-onset diabetes of the young type 8 with exocrine dysfunction (MODY8), also referred to as diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the variable number of tandem repeats (VNTR) of the carboxyl-ester lipase gene (CEL; 114840) on chromosome 9q34.
Maturity-onset diabetes of the young type 8 (MODY8) is characterized by onset of diabetes before age 25 years, with slowly progressive pancreatic exocrine dysfunction, fatty replacement of pancreatic parenchyma (lipomatosis), and development of pancreatic cysts. Patients do not present clinical signs of chronic pancreatitis (summary by Johansson et al., 2018).
For a phenotypic description and discussion of genetic heterogeneity of MODY, see 606391.
The pancreas serves both endocrine and exocrine functions. The endocrine cells are found in the islets of Langerhans; they synthesize insulin (176730) and other hormones, and are involved in the pathogenesis of diabetes mellitus. The exocrine cells of the pancreas produce bicarbonate and digestive enzymes and are involved in the pathogenesis of pancreatic malabsorption. The localization of the islets within exocrine pancreatic tissue is suggestive of an interdependency and crosstalk between these 2 cell populations in their normal and in their abnormal function (Henderson, 1969; summary by Raeder et al., 2006). Hardt et al. (2003) reported a prevalence of 15 to 30% of severe exocrine pancreas dysfunction in patients with diabetes of type I (222100) and type II (125853). Raeder et al. (2006) described 2 Norwegian kindreds with autosomal dominantly inherited diabetes and exocrine pancreas dysfunction. The age at onset of less than 25 years in several of the diabetic cases in the families indicated that the families met the criteria for maturity-onset diabetes of the young. Diabetic subjects had fecal elastase (130120) deficiency (FED) and other clinical parameters compatible with pancreatic exocrine dysfunction. Several family members with and without diabetes had mild abdominal pain and loose stools. The autopsy report of one subject described a macroscopically small and fibrotic pancreas. Histopathologic examination of tissue sections showed pronounced fibrosis and mucinous metaplasia; islet or acinar cells could not be seen. Abnormal pancreatic morphology, namely reduced pancreatic volume, was demonstrated by computerized tomography of the pancreas in all 10 mutation carriers with diabetes and exocrine deficiency. Raeder et al. (2006) noted that the phenotype of this syndrome is distinct and includes both FED and diabetes caused by beta-cell failure, although diabetes is diagnosed later in life.
By genomewide screen in one of their families with diabetes and exocrine pancreatic dysfunction, Raeder et al. (2006) linked diabetes to 9q34 (maximum lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction, they refined the critical region to 1.16 Mb (maximum lod score 11.6). The linkage candidate region contained 24 genes, of which only CEL (114840) was known to be both highly and predominantly expressed in the pancreas.
In each of 2 Norwegian families with autosomal dominant diabetes and pancreatic exocrine dysfunction, Raeder et al. (2006) identified a different single-base deletion causing a frameshift in the variable number of tandem repeats (VNTR) in the CEL gene (114840.0001 and 114840.0002). They also provided data supporting a polygenic role for this region, as common insertions were associated with exocrine dysfunction in an additional group of diabetic subjects.
Using the multiplex PCR method, Torsvik et al. (2010) screened 56 members of the 2 Norwegian families previously studied by Raeder et al. (2006) and confirmed the presence of single-base deletions in the 23 affected individuals in whom they had previously been identified. Torsvik et al. (2010) then analyzed the CEL VNTR in 95 Danish and 146 UK MODY probands, all of whom were negative for mutation in the 7 known MODY genes, but did not find any single-base insertions/deletions in the first 8 repeats of the CEL VNTR. However, 1 Danish proband was identified who had a very short VNTR allele, consisting of only 3 repeats (114840.0003), and in whom sequencing ruled out any other variation in the CEL gene. Of the seven 3-repeat VNTR carriers in the proband's family, 4 had diabetes, 1 had impaired fasting glycemia, and 1 had impaired glucose tolerance; family members with normal VNTR lengths were all normoglycemic. There was no difference in BMI between carriers and noncarriers in the family. Stool samples from 4 carriers showed that 2 had moderate fecal elastase deficiency, whereas the other 2 had normal fecal elastase values. The 3-repeat allele was not found in 233 Norwegian controls, although 1 control individual carried a 4-repeat allele. Torsvik et al. (2010) noted that in the Danish family, the 3-repeat allele appeared to have lower penetrance for diabetes than the mutations previously described in the 2 Norwegian families, and that there was no evidence of cosegregation with exocrine deficiency. They further noted that their controls had not been screened for the absence of diabetes, and stated that it remained unclear whether very short VNTRs were associated with disease or were part of the normal variation of the CEL gene.
Hardt, P. D., Hauenschild, A., Nalop, J., Marzeion, A. M., Jaeger, C., Teichmann, J., Bretzel, R. G., Hollenhorst, M., Kloer, H. U., S2453112/S2453113 Study Group. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus: a multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology 3: 395-402, 2003. [PubMed: 14526149] [Full Text: https://doi.org/10.1159/000073655]
Henderson, J. R. Why are the islets of Langerhans? Lancet 294: 469-470, 1969. Note: Originally Volume 2. [PubMed: 4183910] [Full Text: https://doi.org/10.1016/s0140-6736(69)90171-8]
Johansson, B. B., Fjeld, K., El Jellas, K., Gravdal, A., Dalva, M., Tjora, E., Raeder, H., Kulkarni, R. N., Johansson, S., Njolstad P. R., Molven, A. The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. Pancreatology 18: 12-19, 2018. [PubMed: 29233499] [Full Text: https://doi.org/10.1016/j.pan.2017.12.001]
Raeder, H., Johansson, S., Holm, P. I., Haldorsen, I. S., Mas, E., Sbarra, V., Nermoen, I., Eide, S. A., Grevle, L., Bjorkhaug, L., Sagen, J. V., Aksnes, L., Sovik, O., Lombardo, D., Molven, A., Njolstad, P. R. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nature Genet. 38: 54-62, 2006. [PubMed: 16369531] [Full Text: https://doi.org/10.1038/ng1708]
Torsvik, J., Johansson, S., Johansen, A., Ek, J., Minton, J., Raeder, H., Ellard, S., Hattersley, A., Pedersen, O., Hansen, T., Molven, A., Njolstad, P. R. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. Hum. Genet. 127: 55-64, 2010. [PubMed: 19760265] [Full Text: https://doi.org/10.1007/s00439-009-0740-8]