Biallelic variants in PMM2 cause the rare syndrome of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD). All reported patients have a promoter mutation (c.-167G>T) which is either homozygous or in trans with a PMM2 coding mutation (2).
PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has previously been associated with polycystic kidney disease and 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. These typical clinical features of CDG1A are absent in patients with HIPKD the diagnostic testing of transferrin isoelectric focusing is normal in these individuals clearly separating HIPKD from CDG1A and establishing PMM2 pleiotropy.
Functional studies on the promoter mutation demonstrated decreased transcriptional activity in the kidney cells of a patient and impaired binding of the transcription factor ZNF143 (2). In silico analysis suggests an important role of ZNF143 for the formation of a chromatin loop including PMM2. It has therefore been proposed that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD
Key References
- Cabezas OR, Flanagan SE, Stanescu H, García-Martínez E, Caswell R, Lango-Allen H, Antón-Gamero M, Argente J, Bussell AM, Brandli A, Cheshire C, Crowne E, Dumitriu S, Drynda R, Hamilton-Shield JP, Hayes W, Hofherr A, Iancu D, Issler N, Jefferies C, Jones P, Johnson M, Kesselheim A, Klootwijk E, Koettgen M, Lewis W, Martos JM, Mozere M, Norman J, Patel V, Parrish A, Pérez-Cerdá C, Pozo J, Rahman SA, Sebire N, Tekman M, Turnpenny PD, Hoff WV, Viering DHHM, Weedon MN, Wilson P, Guay-Woodford L, Kleta R, Hussain K, Ellard S, Bockenhauer D. Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. J Am Soc Nephrol. 2017 Aug;28(8):2529-2539. doi:10.1681/ASN.2016121312. Epub 2017 Apr 3. PubMed PMID: 28373276; PubMed Central PMCID: PMC5533241.