ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 2.1 | DOI: 10.1530/ey.15.2.1


To read the full abstract: J Am Soc Nephrol. 2017 Aug;28(8):2529-2539

The association of hyperinsulinaemic hypoglycaemia (HH) and polycystic kidneys has not been reported before. Here, the authors studied 17 patients from 11 different families and found that all patients had a combination HH and polycystic kidneys. The HH was mild and some patients required diazoxide therapy. In contrast the polycystic kidney disease was severe in some patients and a few patients had liver cysts as well. None of the patients described had any neurological phenotype. Recessive loss of function mutations in the phosphomannomutase 2 gene (PMM2) lead to a multisystem disorder called congenital disorder of glycosylation type 1A (CDG1A) with predominately neurological involvement. Prior to this study there have been case reports of HH associated with recessive loss of function mutations in PMM2 gene. However no previous studies have linked the association between HH and polycystic kidneys due to mutations in PMM2. All patients in the current study were found to have a promotor mutation in the PMM2 but none of the patients had any other clinical or biochemical features of CDG1A. The lack of neurological involvement and other clinical features of CGD1A suggested that the promotor mutation is likely to be tissue specific (pancreas and kidneys). The underlying mechanism/s leading to tissue specifc deficiency of PMM2 are not completely known yet but could be related to the promotor mutation altering tissue specific chromotin loop formation. The promotor mutation lead to decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor zinc-finger 143 (ZNF143). This transcription factor preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Further studies will need to establish the molecular basis for the tissue specific loss of function of the promotor PMM2 mutations and the mechanism for the HH and polycystic kidneys.

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