Allelic and Locus Heterogeneity

• Genetic variations (heterogeneity) lead to clinical phenotypes in inherited diseases.

Allelic Heterogeneity

• Multiple alleles at a single locus causes genetic heterogeneity, which is why it's called allelic heterogeneity
• CFTR protein is one of these alleles - it helps to maintain balance of salt and water
• Over 1,000 known mutant alleles of the CFTR gene causes cystic fibrosis
• A hypomorphic allele is a partial loss of function the results in a milder phenotype
• A null allele results in severe phenotypes
• Sickle cell disease mutation in β-globin (Glu6Val) causes clumped hemoglobin at low oxygen

Locus Heterogeneity

• Mutation on a different genetic loci that causes a similar phenotype is called locus heterogeneity

• 100 genes can induce retinitis pigmentosa independently

• Retinitis pigmentosa has autosomal dominant, autosomal recessive, and X-linked origins
• Only one mutant locus is needed for the phenotype to be manifested

Modifier Genes

• Genes which can modify the effect produced by another gene are called modifier genes
• Cystic fibrosis (CF) is mostly caused by mutations in CFTR gene
• Lung disease in CF patients is highly variable due to CFTR modifier genes
• Mutations in BRCA1 and BRCA2 increase breast and ovarian cancer risk; CHEK2 gene mutations further accelerate this risk.

Protein Abnormalities and Genetic Diseases

• Mutations in functional proteins lead to genetic disorders.

Enzymes

• Enzymes are biological catalysts that mediate converting a substrate to a product
• The human genome contains >5,000 genes that encode enzymes
• Enzymopathy is a metabolic disorder from deficiency or abnormality of a specific enzyme
• Hyperphenylalaninemias is a group of disorders characterized by elevated levels of phenylalanine in the blood
• Phenylketonuria (PKU) is a specific form of hyperphenylalaninemia

Hyperphenylalaninemia

• Hyperphenylalaninemia is elevated blood level of phenylalanine (phe), which we get from diet
• Intellectual disability, seizures, behavioral issues are caused by hyperphenylalaninemia
• It is an autosomal recessive disorder due to deficiency of enzyme phenylalanine hydroxylase (PAH) or cofactor tetrahydrobiopterin (BH4)

The biochemical pathway affected in hyperphenylalaninemia:

• Phenylalanine is an essential amino acid converted to tyrosine by phenylalanine hydroxylase
• Tyrosine is an non-essential amino acid

Locus Heterogeneity of The Hyperphenylalaninemias

• Mutations in genes encoding phenylalanine hydroxylase includes Classic PKU, Variant PKU and Non-PKU hyperphenylalaninemia

Phenylketonuria (PKU)

• Classic PKU is an autosomal recessive disorder resulting from mutations in PAH
• Patients with PKU accumulate phe, which damages the central nervous system in early childhood and interferes with the mature brain function, resulting in mental retardation
• There are dietary modifications to prevent phe accumulation in Classic PKU

New Born Screen for Phenylketonuria (PKU)

• PKU can occur at 1 in 2,900 live births
• PKU is the prototype of genetic diseases for newborn screening
• The screening test is performed a few days after birth by taking droplets of blood from a heel prick to analyze the ration [phe]/[trptyr]
• If a test is positive, then it has to be confirmed because delayed initial treatment beyond 4 weeks after birth will effect the intellectual outcome

Variant PKU and Non-PKU Hyperphenylalaninemia

• Variant PKU and non-PKU hyperphenylalaninemia are less severe than classic PKU
• This is due to the residual activity of mutated PAH enzyme

Allelic and Locus Heterogeneity of Hyperphenylalaninemias

• 400 different mutations in PAH gene have been identified worldwide

• Most PKU patients are compound heterozygotes (i.e. with 2 different mutant alleles at the same locus)

Defects in Tetrahydrobiopterin (BH4) Metabolism

• 1-3% of hereditary hyperphenylalaninemia patients have wild-type PAH
• The patients carry defected genes involved in the formation or recycling of the PAH cofactor, BH4

Defects in Tetrahydrobiopterin (BH4) Metabolism (Cont'd)

• BH4 patients still develop neurological problems under administration of a low-phenylalanine diet because it requires 2 other enzymes to function
• These enzymes include : tyrosine hydroxylase and tryptophan hydroxylase