The genetic basis of PKU

The genetic basis of Phenylketonuria

Meera Ravindran, Naomi Elliott and Kimberly Malone Crossley

What are the symptoms?

Introduction

Anxiety linked and Depressive symptoms

Fair and sensitive skin

Problems with muscle control

Vomiting (1)

How are the Symptoms Caused?

The enzyme PAH is required to break down phenylalanine to form Tyrosine, however, the absence of PAH means that not only is there a deficiency of Tyrosine (which is essential), but also there is an excess of Phenylalanine, which is converted into Phenylpyruvate. (2)

A deficiency in Tyrosine is a problem as it is key molecule in the production of Dopamine and many Thyroid hormones.(3) Dopamine is a vital neurotransmitter and a lack of it causes psychological symptoms e.g. depression.(4) The lack of Thyroid Hormones often leads to poor concentration and slowed development.

• Phenylketonuria (PKU) is a rare genetic condition which is congenital- present from birth.
• PKU is caused by a genetic mutation in the hepatic phenylalanine hydroxylase (PAH) gene.
• This means that the chemical Phenylalanine cannot be broken down.
• Currently the only action to be taken against PKU is a heel prick test at birth, and a low protein diet, as protein is rich in phenylalanine, to prevent a build up of phenylalanine. (1)

Mental retardation in PKU is caused by an excess of phenylalanine in the blood. Phenylalanine is a large neutral amino acid and when in excess saturates transport proteins used to cross the blood-brain-barrier. This means that other LNAAs cannot enter the brain and so many essential neurotransmitters cannot be produced.

Metabolic Block

PKU is a 'loss of function' mutation.

• A gene encoding an enzyme in the metabolic pathway is mutated. (7)

Fig 4: New clinical genetics

Why the mutation means there is no working enzyme

Metabolism of the amino acids phenylalanine and tyrosine

Fig 5: New Clinical Genetics

13.5% deletions.

60% missense.

11% splice site mutations.

1.8% insertions.

5% nonsense.

Cataloged Mutations of PAH alleles (8)

Characteristics of an autosomal recessive condition

Genotype- Phenotype

Correlation

Sciver and Waters (1999)

(7)

Conclusion

Fig 6: New clinical genetics

In summary:

* PKU is an autosomal recessive metabolic genetic disorder.

* Both parents must be carriers to pass on the disease.

* The disease is caused by a mutation in the gene for the enzyme PAH, making it non functional

* The symptoms are caused by a deficiency in tyrosine and an excess of phenylalanine.

References

(1) www.nhs.uk/conditions/phenylketonuria/pages/symptoms.aspx

(2) James, William D.; Berger, Timothy G. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier.

(3) Case study 22: New Clinical Genetics

(4) Birkmayer, W; Linauer W, Storung D (1970). "Tyrosin and tryptophan- metabolisms in depression patients". Arch Psychiar Nervenkr 213: 377–387.

(5) AQA Biology AS: Student's Book

(6) http://www.nlm.nih.gov/medlineplus/ency/article/002052.htm

(7) New Clinical Genetics – Andrew Reid and Dian Donnai

(8) Molecular Genetics and Metabolism 104; Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficines: Nenah Blau et al

Enzymes are proteins that have a tertiary structure with an active site.

• Only affects one generation.
• Both parents must be carriers in order for the child to inherit the condition.
• Not X linked.

Punnet Square

1) Random mutation in DNA = change to the base in a gene.

Fig 3: www.stsci.edu

2) A different amino acid is coded for.

3)Primary structure of a polypeptide of the protein is formed.

What sort of mutation is it?

4) Different tertiary structure is formed.

PKU is an autosomal recessive mutation.

"An autosomal recessive disorder means two copies of an abnormal gene must be present in order for the disease or trait to develop." (6)

5)Specific 3D nature of enzyme usually allows the enzyme’s active site to bind to its substrate.

Typical Pedigree for PKU

6) Enzyme substrate complexes form only if the active site is complementary to the substrate.

Key

Normal Female

Normal Male

Carrier Female

Carrier Male

Affected Female

Affected Male

Fig 2: www.accessexcellence.org

7) Mutation means the tertiary structure of the enzyme is altered, hence the active site cannot bind to the substrate and the enzyme is non-functional

(5)

Fig. 1 http://www.contexo.info/DNA_Basics/Protein_Structure.htm