A nonsense SLC16A7 mutation in a family with impaired glucose counter-regulatory responses to hypoglycemia

Abstract

Introduction: The human neurons are important for glucose control since they govern the glucose counter-regulatory response (CRR) during hypoglycemic attacks. Of noted, MCT2, a monocarboxylate transporters abundantly found in ventromedial hypothalamic (VMH) nucleus had been broadly studied in animal models. Its deficiency could lead to a blunted CRR which significantly impact on glucose homeostasis. Nevertheless, the biological and clinical significance of MCT2 deficiency in human is not well studied. Here, we identified a novel nonsense variant in SLC16A7 (which encoded for MCT2) in a patient with recurrent hypoglycemia using clinical whole exome sequencing (cWES). Case: The patient is a 53 years old lady who presented with recurrent ketotic hypoglycemia for 14 years. A fasting test was performed which showed an appropriate insulin response. Urine toxicology studies for oral hypoglycemic agents were all negative. An extended oral glucose tolerance test (OGTT) showed post-prandial hyperglycemia. Glucagon stimulation test (fed state) showed an adequate growth hormone response. Intriguingly, glucagon stimulation repeated after overnight fasting revealed blunted growth hormone and blood glucose responses. Glycogen storage disease type 0 was suspected and the case was referred to us for genetic analysis of recurrent hypoglycemia. Method: Clinical genetic and genomic analyses included conventional PCR and Sanger sequencing and also clinical whole exome sequencing (cWES). The bioinformatics analysis was done using the in-house algorithm. The overall interpretation was based on clinical, biochemical and pathomechanism of the disease-causing genes. Results: No known pathogenic variant was found in known disease-causing genes for hypoglycemia and also for GYS1 gene (for glycogen storage disease type 0). A novel heterozygous nonsense variant, NM_001270622.1:c.1315G>T, p.(Glu439*) was found on exon 6, the last exon of SLC16A7 gene. The c.1315C>T variant is an unreported variant and not found in population database (ExAC and GnomAD). Conclusions: Our work demonstrates a natural human heterozygous MCT2 knockout and its deleterious effect in glucose homeostasis. Since her son is similarly affected, we suggested the SLC16A7-related hypoglycemia is an autosomal dominant condition. SLC16A7 is a novel disease-causing gene for recurrent ketotic hypoglycemia. This patient was put on cornstarch and showed a significant clinical improvement. The novel findings in this case would contribute to the understanding of the expanding spectrum of hypoglycemia. MCT2, is therefore a potential therapeutic target for blood glucose control.