Mutations in Human Genetic Disease


Mutations in human genetic disease include single base‐pair substitutions in coding, regulatory and splicing‐relevant regions of human genes. Other kinds of pathogenic mutations are micro‐deletions, micro‐insertions, duplications, repeat expansions, combined micro‐insertions/deflections (‘indels’), inversions, gross deletions and insertions, and complex rearrangements.

Keywords: mutation; human disease; mutation database; mutation mechanism; mutation consequences; genotype–phenotype correlation

Figure 1.

(a) Spectrum of different types of human gene mutations logged in the Human Gene Mutation Database (see Web Links) as of 10 October 2002 (37031 mutations in 1472 genes). (b) Spectrum of different types of human gene mutations logged as the first reported mutation per disease in Online Mendelian Inheritance in Man (see Web Links) (data as of December 2001).

Figure 2.

Schematic representation of cytosine, 5′ methylcystosine and thymine, and the chemical events involved in the transformation of cytosine to thymine.

Figure 3.

Schematic representation of the slipped mispairing model for deletions and insertions during DNA replication.

Figure 4.

Size distribution of short (fewer than 20 bp) human gene deletions and insertions (Human Gene Mutation Database (see Web Links), 8 July 2002).

Figure 5.

Location of repeat expansions in genes for selected human disorders: UTR: untranslated region; ATG: ATG translation initiation codon; IVS: intervening sequence.

Figure 6.

Homologous unequal recombination between similar regions of sequences A and B. The recombination events cause either deletions or duplications. In the case of a deletion, a hybrid sequence is generated with the first part from sequence A and the second from sequence B. The middle sequence in the duplication product is also a hybrid sequence: the first part is from B and the second from sequence A.

Figure 7.

Genes, duplicons and diseases. Unequal crossing over between homologous sequences (duplicons) produces either deletions or duplications of the DNA between the duplicons. The duplicons are shown by arrows or light boxes. Genes included in the duplications/deletions are shown as dark boxes. STSD: steroid sulfatase deficiency; CMTA1: Charcot–Marie–Tooth disease type A1; HNPP: hereditary neuropathy with liability to pressure palsies; NF1: neurofibromatosis 1; HemoA: hemophilia A; WS: Williams syndrome; SMS: Smith–Magenis syndrome; VCFS: velocardiofacial syndrome; PWS: Prader–Willi syndrome; AS: Angelman syndrome.

Figure 8.

Schematic representation of LINE retrotransposition. A master retrotransposon (full‐length LINE from one chromosomal location) is transcribed to mRNA, then reverse transcribed to double‐stranded DNA and inserted into an adenine‐rich region of another chromosomal location. The transposon has a poly(A) tail and produces a target site duplication: UTR: untranslated region; ORF: open reading frame.

Figure 9.

Common inversion of the factor VIII (F8) gene in severe hemophilia A. (a) Schematic representation of the most distal 1 Mb of Xq. Regions α1, α2 and α3 are 9.5 kb highly homologous DNA elements. The orientations of these sequences are shown by arrows. (b) Intrachromosomal recombination between elements α1 and α3. (c) The crossover results in the inversion of exons 1–22 of the F8 gene.

Figure 10.

Consensus sequences for the donor (5′ splice) and acceptor (3′ splice) sites and the branchpoint. Numbers above or below the nucleotides correspond to frequencies of a given nucleotide in a large number of mammalian splice site sequences. Note that the dinucleotides GT and AG (differently shaded) at the beginning and end of the intron are virtually invariant.

Figure 11.

Examples of splicing abnormalities in introns of human genes. Exons are shown as large boxes and introns as lines between exons. Small squares denote normal 5′ (donor) splice sites and 3′ (acceptor) splice sites. Small circles denote cryptic 5′ and 3′ splice sites. The jagged pointer represents the site of mutation.

Figure 12.

Mutations in the consensus sequences of splice junctions recorded in the HGMD (see Web Links).

Figure 13.

Exon skipping due to nonsense, missense and silent mutations in enhancer splicing elements (ESE). This element is shown as a darkened segment of the middle exon (after Dietz et al. (1993) and Liu et al. (2001)).



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Web Links

Genew: Human Gene Nomenclature Database Search Engine. Gives HUGO approved nomenclature and links to further information about each gene‐bin/nomenclature/

Human Gene Mutation Database (HGMD)

Online Mendelian Inheritance in Man. A catalog of human genes and genetic disorders

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Antonarakis, Stylianos E, and Cooper, David N(Jan 2006) Mutations in Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005471]