Polymorphic PAH alleles
The PAH cDNA sequence contains a large number of recognized polymorphisms
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.
UID 93098260. Figure
C is the complete PAH haplotype listing. It is also available in text
Allele frequency database