The study reported the clinical and genetic characteristics in a Chines patient with c.834C>T (p.L281=) in exon1 in the KCNJ11 gene diagnosed with MODY13. He is a 9-year-old boy, who had presented dry mouth and polydipsia for two weeks, along with elevated blood glucose levels for 8 days. WES shows that this child carries a synonymous heterozygous mutation c.843C>T (p.L281=) in exon 1 of the KCNJ11 gene, and the pathogenicity of this variant is unknown. Genetic verification showed that the variant was derived from the child's mother, and the child had no family history of diabetes.
Synonymous mutations play a key role in the regulation of gene expression and can be pathogenic in certain conditions. In 2020, Walsh19 et al. found that codon-synonymous synapses can affect RNA structure, influence protein folding, and alter the function of molecular chaperones in the dynamic protein homeostasis network, resulting in pathogenicity. The same loci of variation may also exhibit diverse phenotypes due to multiple factors. In 2015, Victoria20 et al screened more than 1400 mutations in Caenorhabditis elegans, and it was found that 20% of the mutation types resulted in phenotypic severity that varied between nematodes, and even some nematodes expressed opposite phenotypes, which are presumed genetic-background-related. In 2015, c.843C>T(p.L281=) of the KCNJ11 was first discovered by Fan17et al. in a Chinese diagnosed with congenital hyperinsulinism. Fan et al. revealed that c.843C>T(p.L281=) reduces exonic splicing enhancers (ESEs), by exonic splicing enhancer finder (http://exon.cshl.edu/ESE/). The current study predicts the RNA structure of the family and reveals that c.843C>T(p.L281=) results in a significant change in the RNA structure of the KCNJ11 (Figure 2B). Nevertheless, the remaining experiments are required to explore the role of this variant in the pathogenesis of CHI and MODY13.
In the pancreatic tissue, the KCNJ11 gene encodes the pore-forming Kir6.2 subunit of pancreatic islet β-cells, and Kir6.2 forms the KATP with the SUR1 subunit of the sulfonylurea receptor in pancreatic β-cells, which plays a key role in the regulation of cellular metabolism and insulin secretion 9-12. Mutations in KCNJ11 can lead to TNDM3, PNDM2, HHF2, and MODY13, meanwhile, KCNJ11 is a high-risk locus for type 2 diabetes 9,12-15.
MODY makes up about 2-5% of the diabetes population and is the most prevalent form of monogenic diabetes 21. The ADAPP recommends that Individuals with atypical diabetes and more than one family member with non-type 1 or type 2 diabetes should be considered for a diagnosis of MODY, but there are currently no definitive diagnostic criteria or processes for MODY 22. Although diagnostic studies of monogenic diabetes and MODY have advanced in recent years, there are few cases of MODY13, with at least 22 cumulative cases of MODY13 patients reported, only 6 of whom are Chinese.
In 2012, Bonnefond et al6 first identified and reported a MODY subtype associated with KCNJ11, denoted MODY13. Since then, 12 KCNJ11 mutant loci have been identified, all of which are missense variants (Figure 3). The child in this study carries a c.843C>T (p.L281=) synonymous variant in the KCNJ11 gene, which is the first reported case of a synonymous variant of MODY13.
MODY13 presents a diverse clinical phenotype, lacking characteristic type 2 diabetes symptoms such as obesity (BMI ranges from 15.2-25.8 kg/m2). The age of onset for the 22 patients with MODY13 documented thus far ranged from 9 to 28 years, with more than half being between 12 and 14 years old. In 4 cases, diabetic ketosis began with thirst, polyhydramnios, and polyuria. 2 patients were diagnosed with MODY13 due to gestational diabetes mellitus detected during the obstetric examination. Diabetes mellitus prevailed in 60% of the patients' families. Aside from blood glucose, there were no significant differences in MODY13 patients' sex, ethnicity, blood pressure, C-peptide, FT4, or insulin-related antibodies when versus KCNJ11 mutation-associated neonatal diabetes mellitus16,23-25.
The treatment strategy for MODY13 can be conducted in two phases: the diabetic ketosis phase and the chronic phase. In the ketosis phase of diabetes, insulin is used to control blood glucose, as in type 1 diabetes, and attention should be paid to monitoring blood glucose and preventing hypoglycemia. Donath et al. reported a case of a 13-year-old patient (weighing 42.3kg) who was intensively treated with an insulin pump26. The maximum insulin dose was 64 IU/d for the whole day at the onset of the disease, and glimepiride 2 mg/d orally was added on the 6th day of insulin pump treatment because of unsatisfactory blood glucose levels. As the patient's blood glucose decreased, the insulin dosage was gradually adjusted downward, and oral glimepiride 1 mg/d was continued after discharge. In the current study, the patient presented with ketosis. After ketone correction treatment, 1 IU of menthol insulin was administered subcutaneously before meals, and 1 IU of detergent insulin was administered subcutaneously at bedtime. After 5 days, the patient was changed to an insulin pump for glucose-lowering treatment due to recurrent hypoglycemia. The dosage was gradually reduced and stopped according to the results of the continuous glucose monitor, and the insulin pump was discontinued after 16 days of use.
In the chronic phase, therapeutic options include a diabetic diet, physical activity, and oral hypoglycemic medicines. Oral hypoglycemic medications for MODY13 include sulfonylureas (e.g. glimepiride), metformin, and acarbose. The average dose of glimepiride is 0.11 (0.07-0.39) mg/kg/day. The average dose of glimepiride for patients with a diagnosis of potassium channel variation <6 months is 0.07 (0.07-0.16) mg/kg/day, and for patients with a diagnosis of potassium channel variation >6 months the average dose of glimepiride is 0.10 (0.04-0.19) mg/kg/day8. Chen et al. reported a patient diagnosed with MODY13 weighing 73 Kg who was treated with metformin 1500 mg/d and acarbose 150 mg/d and converted to glimepiride due to poor glycemic control 27. Glimepiride significantly lowers HbA1C in MODY13 patients compared to other medications (including insulin, metformin, and acarbose). Griscelli et al. attempted to treat MODY13 patients with induced pluripotent stem cells, however, the results were not accurately reported28. The patient in this study maintained satisfactory blood glucose levels without medication after 4 months of insulin cessation (Figure 2), and he is following a diabetic diet with moderate activity.
The prognosis of MODY13 patients varies widely. 25% of MODY13 patients can achieve blood glucose standards without medication and insulin. Neurological symptoms are observed in approximately 20% of patients due to Kir6.2 protein alterations in muscle, nerve, and brain, manifesting as DEND syndrome (developmental delay, epilepsy, and neonatal diabetes mellitus), ADHD (attention-deficit/hyperactivity disorder), autism or selective mutism29. The DEND syndrome was observed by our research team in a child with KCNJ11-associated PNDM 30. In this study, there were no neurological symptoms found in the patients. Hence, patients diagnosed with MODY13 should be monitored for neurological symptoms during follow-up.