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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. Whilst the original Mendelian concept of single gene (monogenic) disorders applies to many skin diseases, which can therefore show classical patterns of inheritance including autosomal dominant (AD), and autosomal recessive (AR). These conditions can show alterations in keratinization ( Table 6.1A ), blistering ( Table 6.1B ), DNA repair ( Table 6.1C ), pigmentation ( Table 6.1D ), appendigeal/vasculature changes ( Table 6.1E ), connective tissues and cancer risk ( Table 6.1F ). Common conditions such as atopy are more complicated 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.

Table 6.1A
Monogenic skin diseases: keratinization anomalies
Gene Protein Gene MIM No. Disease Inheritance
ABCA12 ATP-binding cassette transporter 12 607800 Harlequin ichthyosis, autosomal recessive 4B Autosomal recessive (AR)
ATP2A2 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 108740 Darier disease Autosomal dominant (AD)
ATP2C1 Calcium-transporting ATPase type 2C member 1 604384 Hailey–Hailey disease AD
ERC2/3 ELKS/RAB6-interacting/CAST family member 2/3 126340, 133510 Trichothiodystrophy AR
FLG Filaggrin 135940 Ichthyosis vulgaris AD
RHBDF2 Rhomboid family member 2 614404 Tylosis with oesophageal cancer AD
SPINK5 Serine protease inhibitor Kazal-type 5 6050101 Netherton syndrome AR
Ichthyoses (Adapted from Lemke et al. Dermatology 2014;229(2):55-64.)

Table 6.1B
Monogenic skin diseases: blistering
Gene Protein Gene MIM No. Disease Inheritance
COL17A1 Collagen 17 113811 Epidermolysis bullosa, junctional, non-Herlitz type AR
COL7A1 Collagen 7 120120 Epidermolysis bullosa dystrophica, autosomal recessive AR
COL7A1 Collagen 7 120120 Transient bullous epidermolysis of the newborn AD/AR
KRT14 Keratin 14 148066 Epidermolysis bulosa simplex, Dowling–Meara type AD
Blistering disorders (Adapted from Lemke et al. Dermatology 2014;229(2): 55-64.)

Table 6.1C
Monogenic skin diseases: DNA repair problems
Gene Protein Gene MIM No. Disease Inheritance
XPA Xeroderma pigmentosum, complementation group A 613208 Xeroderma pigmentosum, group A AR
ERCC3 Excision repair cross-complementation group 3 133510 Xeroderma pigmentosum, group B AR
RECQL4 RecQ protein-like 4 603780 Rothmund–Thomson syndrome AR
DNA repair disorders (Adapted from Lemke et al. Dermatology 2014;229(2): 55-64.)

Table 6.1D
Monogenic skin diseases: pigmentation
Gene Protein Gene MIM No. Disease Inheritance
KIT c-kit 164920 Piebaldism AR
NF1 Neurofibromin 1 613113 Neurofibromatosis, type 1 AD
NF2 Neurofibromin 2 607379 Neurofibromatosis, type 2 AD
PTPN11 Tyrosine-protein phosphatase non-receptor type 11 176876 Leopard syndrome AD
SPRED1 Sprouty-related, EVH1 domain containing 1 609291 Legius syndrome AD
TYR Tyrosinase 606933 Albinism, oculocutaneous, type 1 (A/B) AR
Pigmentary disorders (Adapted from Lemke et al. Dermatology 2014;229(2): 55-64.)

Table 6.1E
Monogenic skin diseases: appendage and vascular changes
Gene Protein Gene MIM No. Disease Inheritance
EDAR Ectodysplasin A receptor 604095 Ectodermal dysplasia, hypohidrotic AD
EDARADDEDAR-associated death domain 606603 Ectodermal dysplasia, hypohidrotic AD
GNAQ Guanine nucleotide-binding protein G(q) 600998 Sturge–Weber syndrome Mosaic
KRT81 Keratin 81 602153 Monilethrix AD
KRT83 Keratin 83 602765 Monilethrix AD
RASA1 RAS p21 protein activator 1 139150 Parkes–Weber syndrome AD
Appendigeal and vascular disorders (Adapted from Lemke et al. Dermatology 2014;229(2):55-64.)

Table 6.1F
Monogenic skin diseases: connective tissue and cancer
Gene Protein Gene MIM No. Disease Inheritance
ABCC6 ATP-binding cassette, subfamily C (CFTR/MRP), member 6 603234 Pseudoxanthoma elasticum AR
COL1A1 Collagen 1, alpha 1 120150 Ehlers–Danlos syndrome, type I/VIIA AD
COL5A1 Collagen 5, alpha 2 120215 Ehlers–Danlos syndrome, type I/II AD
ELN Elastin 130160 Cutis laxa AD
FBN1 Fibrillin 1 134797 Marfan syndrome AD
AKT1 Protein kinase B alpha 164730 Cowden syndrome AD
APC Adenomatous polyposis coli 611731 Gardner syndrome AD
FLCN Folliculin 607273 Birt–Hogg–Dube syndrome AD
PTCH1 Patched 1 601309 Gorlin syndrome AD
TSC1 Tuberous sclerosis 1 605284 Tuberous sclerosis complex AD
TSC2 Tuberous sclerosis 2 191092 Tuberous sclerosis complex AD
Connective tissue disorders (Adapted from Lemke et al. Dermatology 2014; 229(2):55-64.)
Note: This is not an exhaustive list. Some diseases are associated with mutations in several genes as shown by hypohidrotic ectodermal dysplasia, monilethrix and tuberous sclerosis complex above. Some gene mutations are associated with different diseases such as collagen 7A1, collagen 1A1 and collagen 5A1. Other diseases have variants e.g. xeroderma pigmentosum groups A–G. Therefore, clinical description is critical and allows complete phenotype genotype correlation.

The human chromosomes

The human genome comprises 23 pairs of chromosomes that are numbered by size ( Fig. 6.1 ). 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.

Fig. 6.1, Chromosome 2.

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