Page 143 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

302 Chapter 8 Gene Expression: The Flow of Information from DNA to RNA to Protein

Figure 8.30 Haploinsufficiency: Some loss-of-function Figure 8.31 Some hypermorphic alleles encode overactive
mutant alleles are dominant to wild-type alleles. The proteins. (a) Achondroplasia, a form of dwarfism, is caused by a
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human GLI3 gene is haploinsufficient. GLI3/GLI3 heterozygotes dominant hypermorphic mutant allele of the FGFR3 gene, FGFR3 G480R .
have extra fingers and toes, a condition known as polydactyly. One (b) The FGFR3 gene encodes a dimeric transmembrane receptor
particular mutant GLI3 allele is a nonsense mutation that changes protein that is normally activated only when it is bound to the small
codon 643 from arginine (R) to stop. (Wild-type GLI3 protein has protein hormone FGF. The tyrosine kinase domain of one activated
1580 amino acids.) FGFR3 subunit adds phosphate groups (P in yellow circles) to the
© Dinodia/agefotostock.com other subunit and vice versa. These phosphorylations initiate a signal
that ultimately stops bone growth. (c) Mutant FGFR3 G480R protein is
always activated, whether FGF is present or not, leading to improper
bone development.
a: © Frazer Harrison/Getty Images
(a) Achondroplasia

643
V T K K Q R G D
Normal allele GTC ACC AAG AAG CAG CGA GGG GAC
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(GLI3 )
Mutant allele GTC ACC AAG AAG CAG TGA GGG GAC
(GLI3) V T K K Q STOP
642
more efficient mutant protein. For example, a hypermorphic G480R
mutation in the human FGFR3 gene results in achondropla­ (b) Normal FGFR (c) Hypermorphic FGFR
sia, the most common form of dwarfism (Fig. 8.31a). The Outside the cell FGF FGF
FGFR3 gene encodes a signaling protein (fibroblast growth receptor no FGF
factor receptor 3) that inhibits bone growth. FGFR3 protein
is normally activated only when a small protein called FGF
(fibroblast growth factor) binds to it (Fig. 8.31b). Most peo­ GG GG RR
ple with achondroplasia carry a mutant allele called PP PP
FGFR3 G480R , which encodes an FGFR3 protein with argi­
nine instead of the normal glycine at amino acid 480. This Tyrosine
single amino acid change causes the mutant protein to be­ kinase
domain
come activated even in the absence of FGF. The mutant pro­ Inside the cell Signal Signal
tein is thus a constitutively active receptor that is activated all Stop bone growth Stop bone growth
the time (Fig. 8.31c). The hypermorphic allele (FGFR3 G480R )
is dominant to the wild­type allele because the mutant pro­ The dominant Huntington disease allele (HD) is an ex­
tein remains active and continues to inhibit bone growth ample of a neomorphic allele that makes a mutant protein.
even if the normal protein is present. Recall from the Fast Forward Box in Chapter 7 (Trinucleo-

tide Repeat Diseases: Huntington Disease and Fragile X
Neomorphic alleles Syndrome) that HD is a polyQ­type trinucleotide repeat
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A rare class of dominant gain­of­function alleles arises gene. Mutant HD proteins have an expanded run of glu­
from neomorphic mutations that generate a novel pheno­ tamine (Q) amino acids, and for unknown reasons such mu­
type. Some neomorphic alleles produce mutant proteins tant HD proteins cause neural degeneration. The HD disease
with a new function, while others cause genes to produce allele is dominant to the normal allele because the presence
the normal protein but at an inappropriate time or place of the normal HD protein (with fewer Qs) does not prevent
(ectopic expression). the mutant HD protein from damaging nerve cells.