A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria

  • Berardino PorfirioEmail author
  • Roberta Sestini
  • Greta Gorelli
  • Miriam Cordovana
  • Alessandro Mannoni
  • Jeanette L. Usher
  • Wendy J. Introne
  • William A. Gahl
  • Thierry Vilboux
Research Report
Part of the JIMD Reports book series (JIMD, volume 30)


We sought to establish rapid and specific genotyping methods for G360R mutation and for seven tightly linked markers in the homogentisate dioxygenase gene to address the question of whether G360R is a mutational hot spot or the result of a founder effect, as it has been repeatedly found in alkaptonuric patients from a geographic isolate in Italy.

For G360R and single nucleotide polymorphism genotyping, high-resolution melting analysis was performed. Microsatellites were analysed by multiplex PCR and capillary electrophoresis. To investigate the natural history of the G360R mutation, we genotyped markers in 52 controls and in 8 unrelated patients from the UK and USA, who also segregated the G360R mutation, and calculated its age using DMLE+2.3 software.

A distinct G360R-bearing haplotype was identified in all patients of Caucasian descent. Estimated mutation age was 545 generations (95% credible set, 402–854), suggesting that G360R arose in an ancestor who lived 8,000–10,000 years BC. Archaeological, historical and demographic data support that a G360R carrier has settled the remote valley where present-day population might have a heterozygote frequency of at least 6%.

Given the late health-threatening complications of alkaptonuria and a cure within reach, inhabitants of this isolate would benefit from screening and genetic counselling.


Alkaptonuria Founder effect Genetic screening Mutation age Ochronosis 



The study was supported by a research grant (Ricerca d’Ateneo 2014) from the University of Florence, Italy, to BP.

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Berardino Porfirio
    • 1
    Email author
  • Roberta Sestini
    • 1
  • Greta Gorelli
    • 1
  • Miriam Cordovana
    • 1
  • Alessandro Mannoni
    • 2
  • Jeanette L. Usher
    • 3
  • Wendy J. Introne
    • 4
    • 5
  • William A. Gahl
    • 4
    • 5
    • 6
  • Thierry Vilboux
    • 4
    • 7
  1. 1.Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, Clinical Physiopathology UnitUniversity of FlorenceFlorenceItaly
  2. 2.Internal Medicine Division, Rheumatology UnitOspedali S. Maria Nuova e PalagiFlorenceItaly
  3. 3.Department of Clinical Biochemistry and Metabolic MedicineRoyal Liverpool and Broadgreen University Hospital TrustLiverpoolUK
  4. 4.Medical Genetics BranchNational Human Genome Research Institute, National Institutes of HealthBethesdaUSA
  5. 5.Office of the Clinical Director, National Human Genome Research Institute, National Institutes of HealthBethesdaUSA
  6. 6.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of HealthBethesdaUSA
  7. 7.Division of Medical GenomicsInova Translational Medicine InstituteFalls ChurchUSA

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