# PHENYLKETONURIA AND THE PHENYLALANINE HYDROXYLASE GENE

> **NIH NIH R37** · BAYLOR COLLEGE OF MEDICINE · 1994 · $425,681

## Abstract

Classical Phenylketonuria (PKU) is a birth defect caused by an
inborn error in amino acid metabolism.  The genetic disorder is
autosomal recessive and is characterized by deficiency of the
hepatic enzyme phenylalanine hydroxylase (PAH) which catalyzes
the hydroxylation of phenylalanine to tyrosine.  The lack of
activity causes elevated phenylalanine level in blood and results in
severe mental retardation of the untreated children.  The
prevalance of PKU among Caucasions is about 1/10,000, and 2%
of the population are carriers of PKU.  We have previously
reported the isolation and characterization of a full-length human
PAH cDNA clone which was used to detect restriction fragment-
length polymorphisms (RFLP's) at the PAH locus and led to the
development of an analytical method for prenatal diagnosis of
PKU.  This method of analysis however, is applicable only to those
families with prior PKU history.  RFLP haplotypes for both
normal and PKU alleles have been determined for Northern
European PKU families.  We observed that 90% of mutant alleles
are restricted to 4 distinct RFLP haplotypes.  Cloning and
sequencing analyses of two to these prevalent mutant alleles have
revealed point mutations affecting normal mRNA splicing and an
amino acid substitution.  Oligonucleotides specific for the
mutations have been used as hybridization probes to demonstrate
that there is a tight association between these mutations and the
particular RFLP haplotypes among mutant alleles due to linkage
disequilibrium.  Additional prevalent PKU genes will be
characterized by sequence analysis, and their respective
frequencies as well as haplotype associations will be determine.
If PKU is indeed caused by a limited number of prevalent mutant
alleles, it will be possible to develop a cassett of specific
oligonucleotides for carrier detection in the population without
prior family history of PKU.  Furthermore, mutant alleles in
individuals of the less severe hyperphenylalaninemic phenotypes
will also be analyzed, which may contain structural mutations
that will provide further insight into the structure-function
relationship of the enzyme.  In addition, the cis-acting elements
in the PAH gene responsible for its liver-specific expression and
regulation will be characterized and the corresponding trans-
acting factors identified.  Finally, we will be characterized and
the corresponding trans-acting factors identified.  Finally, we will
attempt to create an animal model of PKU through transgenic
mouse technology in order to better understand the
pathophysiology of mental retardation in patients.

## Key facts

- **NIH application ID:** 2197519
- **Project number:** 5R37HD017711-12
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **SAM.gov UEI:** FXKMA43NTV21
- **Principal Investigator:** Savio L Woo
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $425,681
- **Award type:** 5
- **Project period:** 1983-04-01 → 1998-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2197519

## Citation

> US National Institutes of Health, RePORTER application 2197519, PHENYLKETONURIA AND THE PHENYLALANINE HYDROXYLASE GENE (5R37HD017711-12). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2197519. Licensed CC0.

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