Phenotype of Variants
microRNA targeting
Synonymous Amino Acid
In the study of Crohn’s disease, Patrick Brest and his colleagues find the variant TTG
compared with CTG in IRGM gene. Both codons are for Leucine and in the microRNA
targeting region1. The variant T will not turn down the protein level of IRGM which has
function of intracellular removal of bacteria. Thus, this variant “T” will cause high level
of IRGM, affecting the process of bacterial digestion and in turn the bacterial numbers
within cells.
In the study of the Multidrug Resistance 1 (MDR1) gene, Michael M. Gottesman etc. has
found a synonymous SNP in exon 26 (C3435T) of MDR1 and this will affect the timing
of co-translational folding and insertion into the membrane because of the rare codon2.
Thus, it will change the structure of sites for substrate and inhibitor interactions.
Non-Synonymous Amino Acid
In the study of Sickle cell anemia, the single nucleotide mutation from GAG to GTG of
β-globin gene coding region results in glutamic acid being substituted by valine at
position 6 ofβ-globin.
DNA methylation
In the study of colon cancer, Markowitz SD has found the methylation happens on the
promoter region of HLTF gene, but not in the lung cancer3. This methylation will inhibit
the HLTF gene expression.
Nucleosome positioning
In the study of Edward C. Stack etc, anthracycline compounds treatment will change the
nucleosome positioning pattern in Huntington’s disease4, upgrading some downstream
genes expression which are repressed by another nucleosome positioning pattern.
Transcription factor binding
Olivier Harismendy etc. has found the risk alleles of SNPs rs10811656 and rs10757278 in
coronary artery disease have disrupted the STAT1 transcription factor binding5, which
will influence the expression of genes in locus 9p21.
Intron splicing
SnRNP: In the research of MOPD I (microcephalic osteodysplastic primordial dwarfism
type 1), Albert de la Chapelle etc. has found four mutations in U4atac snRNA gene
region6. These mutations cause the defective U12-dependent splicing by disrupting the
secondary structure of U4atac snRNA.
Splicing site: In the study of Ichthyosis follicularis, alopecia and photophobia (IFAP)
syndrome, Grzeschik KH has found dysfunction of MBTPS2 (membrane-bound
transcription factor protease site 2) causes the disease7. And one intronic mutation
c.225-6T>A generates a new splicing acceptor site, results in the extension for exon3 by 4
more bases and brings in a premature stop codon.
Untranslated region
In the study of Osteoarthritis (OA), Miyamoto etc. has found the SNP rs143383 [T/C] in
the 5’-UTR of the growth differentiation factor 5 (GDF5) is associated with OA8. GDF5
is a gene important in the development, maintenance and repair of bone tissue. The T
variant in the 5’-UTR will decrease the expression level of GDF5.
Reference:
1. Brest, P. et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of
IRGM-dependent xenophagy in Crohn’s disease. Nat. Genet 43, 242-245 (2011).
2. Kimchi-Sarfaty, C. et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315,
525-528 (2007).
3. Moinova, H.R. et al. HLTF gene silencing in human colon cancer. Proc. Natl. Acad. Sci. U.S.A 99, 4562-4567 (2002).
4. Stack, E.C. et al. Modulation of nucleosome dynamics in Huntington’s disease. Human Molecular Genetics 16, 1164
-1175 (2007).
5. Harismendy, O. et al. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling
response. Nature 470, 264-268 (2011).
6. He, H. et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I.
Science 332, 238-240 (2011).
7. Oeffner, F. et al. Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia
(IFAP) syndrome. Exp. Dermatol 20, 447-449 (2011).
8. Miyamoto, Y. et al. A functional polymorphism in the 5[prime] UTR of GDF5 is associated with susceptibility to
osteoarthritis. Nat Genet 39, 529-533 (2007).