Question

what might cause a trans dominant negative mutation in an enzyme?​

Answer 1

concept of Mendelian dominance is historically based on the

analysis of “qualitative” characters.1 Indeed, the traits chosen by

Mendel gave an all-or-none effect on the phenotype. A myriad of

genetic variants fall within this characterization in that the offspring

is indistinguishable from 1 of the parents. Loss-of-function (LOF)

mutations are in large part recessive in heterozygotes because there

is a sufficient amount or activity of the gene product from the normal

copy for the relevant biochemical reaction or biological process to

take place. Sewall Wright proposed in the 1930s a biochemical expla-

nation for why most LOF mutations in genes encoding enzymes are

recessive.2 A more detailed explanation was subsequently provided

with the metabolic control analysis (MCA). MCA shows that the

robustness of a metabolic pathway to a decrease in the concentration

of an enzyme is due to the fact that the change of metabolic flux sec-

ondary to a change in enzyme concentration is small.3,4 Indeed, the

flux of a pathway often follows a law of diminishing returns as a

function of enzyme concentration. When enzyme levels lead the sys-

tem to operate in the asymptotic part of the curve (Figure 1A,B),

drastic changes in enzyme activity or concentration have very little

effect on flux. Accordingly, for most enzymes, disease-causing var-

iants tend to be recessive.5,6 In contrast to such robustness, there are

plenty of disease-causing variants involving transcription factors

(TFs), macromolecular complexes and signaling molecules that are

dominant/semi-dominant.5–8

The quantitative dimension of dominance depends on the devia-

tion of the heterozygote's phenotypic value from the expected value

based on the phenotypes of the homozygous parents.9 To better

understand the qualitative and quantitative dimensions of dominance,

let us consider that the phenotypic value P (ie, color, weight, length,

concentration of a metabolite, etc) of a diploid individual is a function

of its genotypic value G (ie, TF activity, enzyme concentration, etc),

as well as the effect of modifier genes (M) and the environment (E)

(Figure 1C). This is the well-known P = G + M + E paradigm. This

equation becomes more complicated if we consider the interactions

among G, M and E. We assume that both alleles of a locus will con-

tribute additively to the amount of gene product, although exceptions

can occur (as for dominant negative mutations [DNMs]). When the

genotypic and phenotypic values have a linear relationship, there is

phenotypic additivity and genetic codominance or semidominance,

leading to rather intermediate phenotypes. On the contrary, any non-

linear relationship will elicit dominance of 1 parental phenotype

because P of the heterozygote would not be halfway between the

P of the parental homozygotes.

In this review, we highlight some of the mechanisms underlying

dominance and pinpoint as much as possible, the sources on non-

linearity between genotype and phenotype. Specifically, we explore

Received: 14 June 2017 Revised: 24 July 2017 Accepted: 26 July 2017

DOI: 10.1111/cge.13107

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Clinical Genetics. 2018;93:419–428. wileyonlinelibrary.com