Founder mutation in the PMM2 promotor causes hyperinsulinemic hypoglycaemia/polycystic kidney disease (HIPKD).

Abstract

BACKGROUND:

Polycystic kidney disease with hyperinsulinaemic hypoglycaemia (HIPKD) is a recently described disease caused by a single nucleotide variant, c.-167G>T, in the promoter region of PMM2 (encoding phosphomannomutase 2), either in homozygosity or compound heterozygosity with a pathogenic coding variant in trans. All patients identified so far are of European descent, suggesting a possible founder effect.

METHODS:

We generated high density genotyping data from 11 patients from seven unrelated families, and used this information to identify a common haplotype that included the promoter variant. We estimated the age of the promoter mutation with DMLE+ software, using demographic parameters corresponding to the European population.

RESULTS:

All patients shared a 0.312 Mb haplotype which was absent in 503 European controls available in the 1000 Genomes Project. The age of this mutation was estimated as 105-110 generations, indicating its occurrence around 600 BC, a time of intense migration, which might explain the presence of the same mutations in Europeans around the globe.

CONCLUSION:

The shared unique haplotype among seemingly unrelated patients is consistent with a founder effect in Europeans.

• Authors: Sumaya Islam, Mehmet Tekman, Sarah E Flanagan, Lisa Guay-Woodford, Khalid Hussain, Sian Ellard, Robert Kleta, Detlef Bockenhauer, Horia Stanescu, Daniela Iancu
• Journal: Molecular genetics & genomic medicine (Mol Genet Genomic Med) Vol. 9 Issue 12 Pg. e1674 (12 2021) ISSN: 2324-9269 [Electronic] United States
• PMID: 33811480 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Chemical References

• Phosphotransferases (Phosphomutases)
• phosphomannomutase 2, human

Topics

• Alleles
• Chromosome Mapping
• Family
• Female
• Founder Effect
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Hypoglycemia (diagnosis, epidemiology, genetics)
• Male
• Mutation
• Phosphotransferases (Phosphomutases) (genetics)
• Polycystic Kidney Diseases (diagnosis, epidemiology, genetics)
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Spain
• United Kingdom
• United States