Kesselheim, Anne Lore; (2018) Genetic and molecular studies in Hyperinsulinemic Hypoglycemia and congenital Polycystic Kidney Disease (HIPKD). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: 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 a shared cause. // Methods: We ascertained the clinical phenotype and performed genetic studies. The effect of the identified shared mutation was assessed in vitro. // Results: All patients exhibited HI and enlarged polycystic kidneys. Whole genome linkage analysis in 5 informative families identified a single significant (LOD 6.5) locus on chromosome 16p13.2. A promoter mutation (c.-167G>T) in PMM2 was found in all patients, either homozygous or in trans with PMM2 coding mutations. Yet, typical systemic features of congenital disorder of glycosylation type 1a were absent and the diagnostic test of transferrin isoelectric focusing was normal. 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 for ZNF143 for the formation of a chromatin loop including PMM2 that could affect tissue-specific transcription. In order to investigate this further in a chromatin conformation study a HIPKD cell model homozygous for the promoter mutation was generated with CRISPR-Cas9. // Conclusions: We report a rare disease characterized by the combination of hyperinsulinemic hypoglycemia and polycystic kidney disease. Our findings extend the spectrum of genetic causes for both disorders, provide insights into gene regulation and implicate glycosylation in the disease etiology. The identified promoter mutation appears critical for tissue-specific regulation of PMM2 transcription, leading to an organ-specific phenotype and explaining PMM2 pleiotropy.

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