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

Sumaya Islam1, Mehmet Tekman1, Sarah E Flanagan2

  • 1Department Renal Medicine, University College London, London, UK.

Molecular Genetics & Genomic Medicine
|April 3, 2021
PubMed
Abstract

Insights

Polycystic kidney disease with hyperinsulinaemic hypoglycaemia (HIPKD) is linked to a PMM2 promoter variant. Genetic analysis revealed a shared haplotype in European patients, suggesting a founder effect dating back to 600 BC.

Area of Science:

  • Genetics
  • Human Disease Genetics
  • Population Genetics

Background:

  • Polycystic kidney disease with hyperinsulinaemic hypoglycaemia (HIPKD) is a rare genetic disorder.
  • It is caused by a specific variant in the PMM2 gene promoter (c.-167G>T).
  • Affected individuals identified to date are of European ancestry, hinting at a potential founder effect.

Purpose of the Study:

  • To investigate the genetic origins of HIPKD.
  • To determine if a common ancestor carried the PMM2 promoter variant.

Main Methods:

  • High-density genotyping was performed on 11 patients from seven families.
  • A common haplotype containing the PMM2 promoter variant was identified.
  • The age of the mutation was estimated using DMLE+ software with European demographic data.

Main Results:

  • A shared 0.312 Mb haplotype was found in all HIPKD patients, absent in 503 European controls.
  • The PMM2 promoter mutation is estimated to be 105-110 generations old, originating around 600 BC.
  • This timing coincides with a period of significant European migration.

Conclusions:

  • The shared haplotype strongly supports a founder effect for HIPKD in the European population.
  • The ancient origin of the mutation may explain its presence in geographically dispersed European individuals.
Keywords:
PMM2 genefounder effecthyperinsulinismhypoglycaemiapolycystic kidney diseasepromoter

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