Abstract Pseudoxanthoma elasticum (PXE) is a herita- ble elastic tissue disorder recently shown to be attribut- able to mutations in the ABCC6 (MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A no- table exception however is the prevalence of PXE among South African Afrikaners. A previous report has sug- gested that a founder effect may explain the higher preva- lence of PXE in Afrikaners, a European-derived popula- tion that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplo- types and six different disease-causing variants were iden- tified. Three of these mutant alleles were missense vari- ants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-de- scent, indicating a founder origin of PXE in this popula- tion. Introduction Pseudoxanthoma elasticum (PXE, MIM 177850, MIM 264800) is a heritable connective tissue disorder charac- terized by the accumulation of morphologically abnormal and mineralized elastic fibres in dermal, cardiovascular and ocular tissues (Uitto and Shamban 1987). The dermal phenotype is the most prevalent characteristic of PXE and is frequently associated with dramatic ocular and vascular symptoms (Nishida et al. 1990; Lebwohl et al. 1993; Weenink et al. 1996). Abnormally calcified elastic fibres accumulate in the mid-dermis typically producing yellow- ish papules associated with laxity and loss of elasticity and are mainly located within flexural areas particularly the neck, axilla, antecubital fossa and groin (Uitto and Shamban 1987; Neldner 1988; Uitto et al. 1998). Similar arterial changes within the internal elastic lamina fre- quently cause premature peripheral vascular occlusive disease (Nishida et al. 1990; Lebwohl et al. 1993). An- gioid streaks, the other hallmark of PXE, result from the fragmentation and calcification of elastic fibres within Bruch’s membrane. These changes in this elastic mem- Olivier Le Saux · Konstanze Beck · Christine Sachsinger · Carina Treiber · Harald H. H. Göring · Katie Curry · Eric W. Johnson · Lionel Bercovitch · Anna-Susan Marais · Sharon F. Terry · Denis L. Viljoen · Charles D. Boyd Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa Hum Genet (2002) 111 : 331–338 DOI 10.1007/s00439-002-0808-1 Received: 17 April 2002 / Accepted: 8 July 2002 / Published online: 7 September 2002 ORIGINAL INVESTIGATION Electronic-database information: accession numbers and URLs for data in this article are as follows: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi. nlm.nih.gov/Omim/ (for PXE [MIM 177850, MIM 264800]) Genbank (for BAC clone CIT987SK-A-962B4 [accession number U91318], for ABCC6 cDNA [accession number NM_001171], for PPOX cDNA [accession number U26446], for FANCC cDNA [accession number XM_047190], for FANCA cDNA [accession number NM_000135]) The mutations reported here have been submitted to the Human Gene Mutation Database (HGMD, http://archive.uwcm.ac.uk/ uwcm/mg/hgmd0.html), temporary accession number H972168 O.Le Saux · K. Beck · C. Sachsinger · C. Treiber · C.D. Boyd (✉) Pacific Biomedical Research Center, University of Hawai’i, Honolulu, Hawaii, USA e-mail: cbkc08901@aol.com, Tel.: +1-808-9566341, Fax: +1-808-9569481 H.H.H. Göring Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex., USA K. Curry · E.W. Johnson Barrow Neurological Institute, Phoenix, Ariz., USA L. Bercovitch Department of Dermatology, Brown University, Providence, R.I., USA A.-S. Marais PXE International (South Africa), Mowbray, South Africa S.F. Terry PXE International, Sharon, Mass., USA D.L. Viljoen Department of Human Genetics, University of Witwatersrand, Johannesburg, South Africa © Springer-Verlag 2002