title: A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Biomedical Sciences "Mario Serio", Clinical Physiopathology Unit, University of Florence, Viale Gaetano Pieraccini 6, 50139, Florence, Italy. nporfirio@unifi.it.
authors.forename: Berardino
authors.initials: B
authors.lastname: Porfirio
authors.affiliation: Department of Clinical and Experimental Biomedical Sciences "Mario Serio", Clinical Physiopathology Unit, University of Florence, Viale Gaetano Pieraccini 6, 50139, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sestini
authors.affiliation: Department of Clinical and Experimental Biomedical Sciences "Mario Serio", Clinical Physiopathology Unit, University of Florence, Viale Gaetano Pieraccini 6, 50139, Florence, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Gorelli
authors.affiliation: Department of Clinical and Experimental Biomedical Sciences "Mario Serio", Clinical Physiopathology Unit, University of Florence, Viale Gaetano Pieraccini 6, 50139, Florence, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cordovana
authors.affiliation: Internal Medicine Division, Rheumatology Unit, Ospedali S. Maria Nuova e Palagi, ASL 10 Firenze, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mannoni
authors.affiliation: Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool and Broadgreen University Hospital Trust, Liverpool, UK.
authors.forename: Jeanette L
authors.initials: JL
authors.lastname: Usher
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Introne
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA, 22042, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
keywords: Alkaptonuria; Founder effect; Genetic screening; Mutation age; Ochronosis