Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

Abstract

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence (HIPKD) in 17 children from 11 unrelated families suggested the existence of a previously unrecognized genetic disorder. Whole genome linkage analysis in 5 informative families identified a single significant (LOD 6.5) locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, a promoter mutation (c.-167G>T) in PMM2 was found in all patients, either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has previously been associated with polycystic kidney disease and we show that deglycosylation in pancreatic β-cells alters insulin secretion.Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multi-system disorder with prominent neurological involvement. Yet the typical clinical features of CDG1A were absent in our patients and the diagnostic test of transferrin isoelectric focusing was normal, clearly separating HIPKD from CDG1A and establishing PMM2 pleiotropy. The promoter mutation showed decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggests an important role of ZNF143 for the formation of a chromatin loop including PMM2.We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

Identification of Degree of Ordering in Spinel LiNi0.5Mn1.5O4 through NMR and Raman Spectroscopies Supported by Theoretical Calculations

“…40 The Raman intensities were determined using the analytical Coupled Perturbed Kohn-Sham (CPKS) method. 41,42 High-density k-mesh was employed as well as large Gaussian-type basis sets: 22,40-43 6-11 for Li, 86-411 (d41) for Mn, 86-411 (d41) for Ni, and 8-411 for O 38,43 , respectively to ensure the convergence of the optical properties.…”