Molecular genetics and the skin

Published on 04/03/2015 by admin

Filed under Dermatology

Last modified 22/04/2025

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Molecular genetics and the skin

Recent and rapid advances in genetics have had an impact on our understanding of skin diseases. The Human Genome Project has now mapped all human genes, of which there are about 35 000. Genetics has been found to be more complicated than the original Mendelian concept, and common conditions such as atopy occur as a result of a complex interaction between multiple susceptibility genes and the environment. An average pregnancy carries a 1% risk of a single gene disease and a 0.5% risk of a chromosome disorder, but genetically influenced traits, e.g. atopy, are much more common.

The human chromosomes

The human genome comprises 23 pairs of chromosomes that are numbered by size (Fig. 1). Chromosomes are packets of genes with support proteins in a large complex. The karyotype is an individual’s number of chromosomes plus their sex chromosome constitution, i.e. 46XX for females and 46XY for males. The phenotype is the expression at a biological level of the genotype, e.g. blue eyes or atopy.

Molecular methods

DNA sequence variations can be identified by the consequent change in polymerase chain reaction (PCR) amplification product size (Fig. 2), loss or gain of restriction endonuclease cutting, or sequence analysis. In recent years, DNA sequencing has become a high-throughput technology that has led to the concept of ‘whole genome sequencing’ studies of healthy versus controls. As this technique is so powerful, smaller numbers are required.

To establish which molecular pathways may be important in disease pathogenesis, gene chip arrays and ‘next generation sequencing’ allow detailed and quantitative analysis of the transcribed genes in a diseased tissue (transcriptome). The transcribed genes are subject to further regulation by RNA degradation, silencing and inhibition. Thus, study of the protein repertoire in the diseased tissue (proteomics) may also be undertaken.

Molecular techniques can be used to:

Table 1 Skin conditions or characteristics with definite or probable gene localities on the chromosomes

Chromosome site Disease or characteristic
1p34 Porphyria cutanea tarda: enzyme (p. 46)
2q31 Ehlers–Danlos syndrome: collagen III (p. 93)
3p21.3 Dystrophic epidermolysis bullosa: collagen VII (p. 91)
4, 4p Red hair colour, psoriasis (Psors3 gene)
6p21.3 Psoriasis (Psors1 gene: 30% of susceptibility)
9p21 Familial malignant melanoma: kinase inhibitor (p. 102)
9q22.3 Xeroderma pigmentosum (p. 93)
9q34 Tuberous sclerosis: hamartin (p. 92)
11q12 Atopy: asthma and rhinitis: IgE response (p. 36)
12q13 Epidermolysis bullosa simplex: keratin 5 (p. 91)
12q23 Darier’s disease: adenosine triphosphatase (p. 90)
14q11.2 Ichthyosis: transglutaminase (p. 90)
15q11.2 Oculocutaneous albinism: homologue (p. 74)
17q11.2, 17q25 Neurofibromatosis NF1, psoriasis (Psors2)
17q21.31 Ehlers–Danlos syndrome: collagen I (p. 93)
19 Green/blue eye colour, brown hair colour
21 trisomy Down syndrome (p. 93)
Xq28 Incontinentia pigmenti: nuclear factor (NF)-κB modulator (p. 93)
Xq22.32 X-linked ichthyosis: steroid sulphatase (p. 90)

Forms of inheritance

An individual with two different genes (alleles) at a particular locus is heterozygous, and one who has identical alleles is homozygous. Genes borne on chromosomes other than X and Y are autosomal, whereas those on X and Y are sex linked. Factors governing genetic penetrance are unclear.

Inheritance of specific skin disorders

In psoriasis (p. 24) and atopic eczema (p. 36), a family history is common, but the exact mode of inheritance is unclear. Psoriasis may be inherited polygenically or by an autosomal dominant gene with incomplete penetrance. Atopic eczema has recently been shown to be strongly associated with chromosome 1q21 mutations in the gene encoding the epidermal protein, filaggrin. Inheritance patterns in the rarer conditions are often clearer (Table 2). Epidermolysis bullosa simplex and dystrophica (p. 91), the porphyrias (p. 46), the Ehlers–Danlos syndromes (p. 93) and some other conditions may be dominantly or recessively inherited.

Table 2 The inheritance of selected skin disorders

Inheritance Disorder
Autosomal dominant
Autosomal recessive
X-linked recessive X-linked ichthyosis (p. 90)
X-linked Incontinentia pigmenti (p. 93)

Some dermatoses are associated with polymorphisms in the human leucocyte antigen (HLA) complex on chromosome 6 (p. 11). These tend to show polygenic inheritance and an association with autoimmunity.