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Mutation map


Polymorphic PAH alleles

The PAH cDNA sequence contains a large number of recognized polymorphisms (Figure A), with the likelihood of more yet to be recognized in the introns when the full genome sequence for PAH is known. Polymorphisms occur in three forms: i) Biallelic restriction fragment length polymorphisms (RFLPs), named from the corresponding restriction enzyme (BglII; PvuIIa; PvuIIb; EcoRI; Msp1; Xmn1; and EcoRV). With the exception of the EcoR sites, which require analysis by Southern blotting, PAH RFLPs can be analyzed by methods based on PCR amplification; ii) Multiallelic polymorphisms, which include a hypervariable sequence (VNTR) of tandemly repeated 30-bp cassettes harbouring at least 10 alleles (differing by number of repeats) in a HindIII fragment 3 kb downstream from the last exon in PAH ; and a series of short tandem (tetranucleotide, (TCTA)n) repeats (STR) harboring at least 9 alleles in the third intron of PAH ; iii). Single nucleotide polymorphisms (SNPs) which are silent (non RFLP) alleles, for example: c.1546g->a which occurs at ~ 0.20 frequency in the 3 UTR of PAH on both mutant and normal chromosomes; and a silent c.696A->G polymorphism (q=0.08 - 0.63) in codon 232 (Q232Q).

Polymorphic haplotypes. RFLP, STR, and VNTR alleles can be combined to generate extended PAH-locus haplotypes. A "mini-haplotype" comprising only the STR, Xmn1, and VNTR alleles is an alternative because it is informative, accessible to PCR-based analysis and easy to obtain. The extended PAH haplotypes are named with Arabic numbers and at least 87 are known. A matrix (Figure B, courtesy Mary Fujiwara) summarizes extended PAH haplotype configurations derived from 7 biallelic and 2 multiallelic sites in a population of European descent; the variety of configurations would be vastly increased if SNPs were included.

Whereas several thousand different extended polymorphic PAH haplotypes could be generated from combinations of RFLP, STR and VNTR alleles, far fewer have actually been observed on human chromosomes; Figure B includes an observed frequency distribution of haplotypes on a set of normal chromosomes from a defined European population; only a few haplotypes are prevalent; most are uncommon, and this is typical of all human populations analyzed up to now. The apparent shortage of PAH haplotypes is explained by linkage disequilibrium across the 100 kb region of the extended haplotype. PAH haplotype heterogeneity is much greater on mutant and normal chromosomes in Europeans than it is on chromosomes in Asians. PAH haplotype diversity is greater in African populations than in Europeans assuming the latter are descendants of a small founding group emerging out of Africa some 100,000 years ago (Kidd J, Kidd K, pers. comm. 1998).

Particular PAH haplotypes tend to harbour the prevalent disease-causing mutations in European populations, for example: haplotype 7 is usually associated with the prevalent PKU-causing mutation G272X in Norway; haplotype 2 with R408W in Eastern Europe; haplotype 1 with R408W on the Northwestern fringes of Europe; haplotype 3 with IVS12nt1 in Northern Europe; haplotype 9 with I65T in Western Europe and the Iberian peninsula; haplotype 6 with IVS10nt-11 in Anatolia, Southeastern Europe and the Mediterranean region. Codominant segregation of polymorphic PAH haplotypes, in association with the known mutant genotype, when the latter has been ascertained from a propositus, is compatible with carrier detection and prenatal diagnosis, without recourse to mutation analysis itself.

Polymorphic haplotypes at the PAH locus can be used to study human evolution and the histories of human populations without reliance on disease-causing alleles. Although the latter can be particularly informative in this regard, they are much rarer and therefore may not be available for this type of analysis; in Africa, for example. Divergence between African, European and Asiatic populations has been documented by PAH haplotype analysis; the ancestral haplotypes on which some modern haplotype configurations arose can be postulated; the origins, by geographic region and population, of a particular allele surmised; the particular genetic structure (at the PAH locus) of a population described by its haplotype configuration and used to unravel demographic histories; and haplotypes can serve as migration traces over large geographic regions and time-frames. [Extracted from Scriver CR and Kaufman S. Chapter 77 in The Metabolic and Molecular Bases of Inherited Disease, 8th edition. McGraw-Hill (Med Pub. Div). New York. pp. 1667-1724].

The following  information has been adapted by Susan Byck from: Eisensmith R.C., and Woo S.L.C., Am.J.Hum.Genet. 51:1445-1448,1992. Medline UID 93098260. Figure C is the complete PAH haplotype listing. It is also available in text format.

ALFRED Allele frequency database

Copyright 2003 DeBelle Laboratory - Created [2002.10.17.208076] - Updated [2009.08.31]