One Gene, One Enzyme

"One Gene, One Enzyme"
Genotype / Phenotype

In Principle: Proteins are the products of genes.
                        Proteins catalyze biochemical reactions.
                        Such reactions produce phenotypes, either directly or indirectly.
                        Different alleles produce different phenotypes

Interaction between alleles in diploid organisms is the subject matter of Classical Genetics

Biochemical Basis of Human Genetic Diseases

    Diploid organisms have two alleles at each gene locus, one from each parent
      Interactions between alleles at a locus are the subject matter of classical (Mendelian) genetics

   "Online Mendelian Inheritance in Man" (OMIM) database
            Examples from human biochemical genetics: "Inborn errors of metabolism"
      First three involve disruptions of phenylalanine metabolism

Phenylketonuria (PKU) (Folling 1934) (OMIM citation 261600)
          phenylalanine & by-products accumulate in Central Nervous System

mental retardation
      A defect of phenylalanine hydroxylase
          phenyalanine metabolized to phenylpyruvic acid in alternative pathway

   Detection & treatment
         biochemical testing of newborns: Guthrie Test [Homework #18]
           phenylalanine-restricted diet corrects inborn condition (Euphenics)
               Maternal PKU occurs in children high fetal [phe] born to treated, asymptomatic mothers
         [ Further information on PKU & related Inborn Errors of Metabolism ]

PKU arises from genetic variation at the Phenylalanine Hydroxylase (PAH) gene locus
    Important: This gene is not a gene "for" PKU: it is a gene "for" PAH
    Diploid humans each have two alleles at this locus
        Allelic variants produce different levels of PAH activity
       Consider diploid combinations of three (hypothetical) alleles: A, B, & C :

Phenotypic consequences of allelic interactions at the PAH locus

Genotype	PAH Activity	[phe] uM	PKU Phenotype
AA	100%	60	Standard (non-PKU)
AB	30%	120	Standard (non-PKU)
CC	5%	200 ~ 300	Hyperphenylalanemia: no special diet required
BB	0.3%	600 ~ 2400	Classic PKU: special diet required

   [Alleles B & C) arise from DNA mutations in the PAH gene]

PKU was originally described as a "recessive" genetic disease: What does this mean?

      AB genotype shows same PKU phenotype as AA genotype: non-PKU
   A allele shows haplosufficiency:
                    one "allele's worth" of product is sufficient for standard phenotype
         or, expression of A allele "masks" expression of B allele
                A is described as "dominant" to B in influencing PKU phenotype
                B is described as "recessive" to A
                    and BB phenotype is different from AA / AB phenotype: PKU

        but PAH activity phenotype of AB is intermediate between AA & BB
                 AB phenotype is closer to BB than AA (0% < 30% << 100%)
                 Is B therefore an "incomplete dominant" to A ?

        and B produces a higher [phe] phenotype than A:
                Is B therefore "dominant" to A ?

    Distinguish molecular versus phenotypic expression (Homework #19)

Homework #20

Predict the PAH activity, [phe], & PKU phenotypes of the AC and CB genotypes.

Explain your reasoning.

Would you expect to find a dominant mutation in this pathway?
Why or why not?
What might be the phenotypic consequence of such a mutation?

Other molecular disorders of Phenylalanine metabolism
    Alkaptonuria (OMIM 203500): an illustration of "Classical" versus "Reverse" Genetics
                                                      an introduction to Ascertainment Bias
    Oculo-cutaneous Albinism (OMIM 203100)