To read the full abstract: Am J Med Genet A. 2019 Apr;179(4):542551.
This study describes 7 individuals with hyperinsulinemic hypoglycemia caused by NSD1 gene mutations with 3 having persistent hyperinsulinemic hypoglycemia.
The underlying mechanisms that lead to hyperinsulinaemic hypoglycemia in Sotos syndrome are not known. Since most of the previous reported cases of Sotos syndrome are due to microdeletions in the 5q35 region it is assumed that deletion of specific genes in this region lead to HH. In this study, the authors report 7 patients with point mutations in the NSD1 gene and either transient or persistent HH. These observations suggest that the NSD1 gene has a role in glucose and insulin homeostasis and that other genes might not be involved in the microdeletions around 5q35.
The functions of NSD1 have not been fully elucidated. It is thought to act as a transcriptional intermediary factor capable of both negatively and positively influencing transcription depending on the cellular context. NSD1 is expressed in human pancreatic beta-cells as shown by single cell RNA analysis and bulk islet analysis. NSD1 is a regulator of the chromatin structure and gene expression as it catalyzes specific types of histone methylation, and contributes to the initiation, maintenance, or termination of gene activation or repression. The NSD1 molecule has no DNA-binding domain, but binds to both cofactors and methylated histones, suggesting that it exhibits features of a cofactor complex. It is possible that the disrupted interaction between NSD1 and histones or cofactors may directly cause the abnormal expression of insulin. NSD1 may also be associated with beta cell-specific transcription factor(s) to suppress the expression of the insulin gene. Another explanation of the hyperinsulinemia in patients with Sotos syndrome includes the involvement of factors that influence the biological function of insulin in vivo (Matsuo et al.).
The important message from this study is that patients with Sotos can present with atypical features and blood glucose levels should be checked in these patients. Further research on the role of NSD1 in beta-cell physiology should shed some insights into the mechanisms of unregulated insulin secretion.
Reference: Matsuo T, Ihara K, Ochiai M, Kinjo T, Yoshikawa Y, Kojima-Ishil K, Noda M, Mizumoto H, Misaki M, Minagawa K, Tominaga K, Hara T. Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am J Med Genet A 2013 Jan;161A(1):347.