If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Pharmacology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Pharmacology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Pharmacology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
The 42nd Annual Symposium on the Biology of the Skin, entitled “The Genetics of Skin Disease”, was held in Snowmass Village, Colorado, in July 1993. That meeting presented the opportunity to discuss how modern approaches to molecular genetics and molecular biology could be applied to understanding the mechanisms of skin diseases. The published proceedings of this meeting stated that “It is an opportune time to examine the genetics of skin disease” (
). Indeed, this meeting just caught the wave of early pioneering studies that have helped us to understand the molecular basis of a large number of genodermatoses. This overview presented in the 50th Annual Symposium on the biology of the skin, highlights the progress made in the molecular genetics of heritable skin diseases over the past decade.
The recent progress made in molecular genetics of heritable skin diseases is abundantly evident from the present vantage point, as reviewed in the 50th Annual Montagna Symposium on the Biology of Skin, also held in Snowmass Village, Colorado, in July 2001. At the time of our previous meeting, almost a decade ago, the molecular basis of the prototypic genodermatoses, such as epidermolysis bullosa (EB), was beginning to emerge as the first mutations in the keratin 5 and 14 genes in the simplex forms and in the type VII collagen gene in the dystrophic variants had just appeared in the literature (
A homozygous insertion-deletion in the type VII collagen gene (COL7A1) predicting a truncated protein in the Hallopeau-Siemens form of recessive dystrophic epidermolysis bullosa.
). At the same time, there was very little understanding of the molecular basis of complex multisystem disorders, such as pseudoxanthoma elasticum (PXE), the Ehlers–Danlos syndrome, and the Marfan syndrome. Over the ensuing years, this situation has very quickly changed, and there has been tremendous progress towards understanding the molecular basis of different forms of single-gene heritable disorders. In fact, mutations have now been identified in more than 200 distinct genes in a manner that the genetic lesions explain the spectrum of phenotypic manifestations encountered in these diseases (Table I,
If a recent, comprehensive review on the molecular genetics of the corresponding disease exists, the reference is included. In other cases, pertinent original publications are referenced.
Lipoxygenase-3 (ALOXE3) and 12 (R) -lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.
Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).
Heritable diseases affecting the elastic tissues. Cutis laxa, pseudoxanthoma elasticum and related disorders.
in: Rimoin D.L. Connor J.M. Pyeritz R. Korf B.R. Emery & Rimoin's Principles, Practice of Medical Genetics. Vol, 3. New York,
Churchill Livingstone2002: 4044-4070
Heritable diseases affecting the elastic tissues. Cutis laxa, pseudoxanthoma elasticum and related disorders.
in: Rimoin D.L. Connor J.M. Pyeritz R. Korf B.R. Emery & Rimoin's Principles, Practice of Medical Genetics. Vol, 3. New York,
Churchill Livingstone2002: 4044-4070
in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects 2nd edn. New York,
Wiley-Liss2002: 431-523
Molecular basis for the progeroid variant of Ehlers–Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene.
Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase.
Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase: identification of the first molecular lesion causing Farber disease.
a EB, epidermolysis bullosa; PPK, palmoplantar keratoderma.
b For details of the genes, see Online Mendelian Inheritance in Man (OMIM) database, www.ncbi-mim.nih.gov/Omim/, or the corresponding references.
c If a recent, comprehensive review on the molecular genetics of the corresponding disease exists, the reference is included. In other cases, pertinent original publications are referenced.
d For details on EB, see Table II and the text. (Modified from
Examination of the mutation database in these diseases has revealed a number of genes that could have been predicted, on the basis of clinical, histopathologic, immunohistochemical, and/or ultrastructural analysis, to serve as candidate gene/protein systems. For example, in the case of EB, we initially postulated that mutations in the structural genes expressed within the cutaneous basement membrane zone (BMZ) could harbor mutations that explain the fragility of the skin at the dermal–epidermal junction (
). This postulate has now been verified by demonstration of a large number of distinct mutations in as many as 10 different genes expressed within the cutaneous BMZ (see below). At the same time, a number of mutated genes have turned out to be rather surprising, and the exact relationship of the mutations in the affected genes and their consequences at the clinical and morphologic level are not well understood. An example of such conditions is PXE, in which we and others have recently demonstrated mutations in the ABCC6 gene encoding the MRP6 protein, a putative ATP-dependent transmembrane pump of unknown function (
). Surprisingly, this gene is expressed primarily, if not exclusively, in the liver and the kidneys, and the pathomechanistic links between the underlying genetic mutations in ABCC6 and calcification of pleiomorphic elastic structures in the skin, the eyes, and the arterial blood vessels remain unclear.
To illustrate the progress made in understanding the genetic basis of heritable skin diseases in general, we will highlight two specific disease entities, in which we have been major contributors, namely epidermolysis bullosa and pseudoxanthoma elasticum.
The Paradigm of EB
An example of the conditions in which spectacular success has recently been made is EB, a heterogeneous group of mechano-bullous disorders manifesting with blistering and erosions of the skin (
Revised classification system for inherited epidermolysis bullosa. Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa.
in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects 2nd edn. New York,
Wiley-Liss2002: 687-725
). The extent of skin involvement, combined with a number of extracutaneous manifestations encountered in different variants of EB, can cause considerable morbidity and, in some cases, premature demise of the affected individuals. EB has been traditionally divided into three broad categories based on the level of tissue separation within the cutaneous BMZ: the simplex, junctional, and dystrophic types (
Revised classification system for inherited epidermolysis bullosa. Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa.
). More recently, we have proposed an additional subgroup, the hemidesmosomal variants of EB, which include generalized atrophic benign EB, EB with pyloric atresia, and EB with muscular dystrophy (
). Examination of the mutation database suggests that the types and combinations of the mutations, their positions along the affected proteins, and the dynamic interplay of the mutant alleles on the individuals' genetic background will determine the continuum of severity in the spectrum of clinical manifestations of EB.
Table IIMolecular heterogeneity of epidermolysis bullosa
EB, epidermolysis bullosa; EB-MD, EB with muscular dystrophy; EB-PA, EB with pyloric atresia; GABEB, generalized atrophic benign EB.
Cleavage plane
Mutated genes/polypeptides
Chromosomal locus
Affected protein systems/interactions
Simplex
Basal keratinocytes
KRT5/Keratin 5 (K5)
12q13
Keratins 5 and 14, the major components of intermediate filaments expressed in basal cells
KRT14/Keratin 14 (K14)
17q12-q21
Hemidesmosomal
Hemidesmosome–lamina lucida interface
EB-MD
PLEC1/Plectin
8q24
Plectin, located in the inner plaque of hemidesmosomes, interacts with intermediate filaments providing integrity to the basal keratinocytes
EB-PA
ITGA6/α6 integrin
2q24-q31
The subunit components of α6β4 integrin, a transmembrane complex extending from the outer plaque of hemidesmosomes to the lamina lucida
ITGB4/β4 integrin
17q25
GABEB
COL17A1/α1 chain of type XVI collagen (BPAG2/the 180-kDa bullous pemphigoid antigen
10q24.3
Type XVII collagen/the 180-kDa bullous pemphigoid antigen, a transmembrane component of anchoring filaments, traverses lamina lucida providing integrity to the basement membrane zone
Junctional
Lamina lucida
LAMA3/laminin α3-chain
18q11.2
The α3-, β3-, and γ2-chains are subunit polypeptides of laminin 5, located in the lamina densa/lamina lucida interface, interacts with α6β4 integrin and type VII collagen
LAMB3/laminin β3 chain
1q32
LAMC2/laminin γ2-chain
1q25-q31
Dystrophic
Papillary dermis
COL7A1/α1 chain of type VII collagen
3p21.1
Type VII collagen is a major component of anchoring fibrils extending from lamina densa to the papillary dermis
a EB, epidermolysis bullosa; EB-MD, EB with muscular dystrophy; EB-PA, EB with pyloric atresia; GABEB, generalized atrophic benign EB.
Particularly instructive regarding the progress made in understanding the molecular basis of different variants of EB and in explaining the clinical spectrum of the disease are the dystrophic forms of EB (DEB). There is considerable genetic and phenotypic variability in DEB. First, the DEB can be inherited in either an autosomal dominant or autosomal recessive fashion. Second, the clinical severity is highly variable demonstrating a spectrum of manifestations. For example, the most severe form of DEB, the Hallopeau–Siemens type, manifests with mutilating scarring with joint contractures, corneal erosions, esophageal strictures, and propensity to formation of cutaneous squamous cell carcinomas that can lead to premature demise of the affected individuals (
Revised classification system for inherited epidermolysis bullosa. Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa.
). A clinically milder form, the mitis variant of recessive DEB, is characterized by life-long blistering tendency, with limited scarring and less frequent extracutaneous manifestations. In fact, in some cases the clinical severity of mitis recessive DEB can manifest only with subtle nail changes and occasional blistering.
In general, patients with dominantly inherited forms of DEB tend to have a relatively mild phenotype, and they often show blistering only on the hands and feet, and occasionally there is only minimal cutaneous involvement with nail dystrophy. Thus, the dominantly inherited DEB can be indistinguishable from the mitis recessive DEB on clinical, immunohistochemical, and ultrastructural grounds. Specifically, besides the mild clinical features, immunohistochemistry is positive, although occasionally attenuated, for type VII collagen epitopes, and diagnostic transmission electron microscopy usually reveals the presence of some anchoring fibrils which, however, can be either reduced in number or morphologically altered in both forms of DEB. This situation then poses a diagnostic dilemma concerning the mode of inheritance, de novo dominant vs mitis recessive DEB (
). As discussed below, this dilemma can be resolved by DNA analysis of the mutations in the type VII collagen gene (COL7A1).
Distinct mutations have been disclosed in COL7A1 both in DDEB and RDEB in a large number of families (Table II). A characteristic genetic lesion in the most severe recessive DEB is premature termination codon-causing mutation, resulting either from a nonsense mutation or from small out-of-frame insertions or deletions or splicing mutations in both COL7A1 alleles. These mutations are distributed along the entire type VII collagen molecule, and most of them are family specific, only a few of them being recurrent (Figure 1). A characteristic genetic lesion in dominantly inherited forms of DEB is a glycine substitution mutation in one allele of COL7A1 residing within the collagenous domain of the proα1(VII) chain (Figure 1). The mutated polypeptides are full-length and capable of assembling into triple-helical collagen molecules in combination with wild-type polypeptides (
Epidermolysis bullosa. The disease of the cutaneous basement membrane zone.
in: Scriver C.R. Beaudet A. Valle D. Sly W.S. Vogelstein B. Kintler K.W. Childs B. The Metabolic and Molecular Bases of Inherited Disease 8th edn. New York,
McGraw-Hill2001: 5655-5674
); however, the presence of the glycine substitution destabilizes the collagenous triple-helix, and the presence of the mutated polypeptides causes a dominantly inherited disease through dominant negative interference. Thus, analysis of the type of mutations and their combinations along the type VII collagen gene provides an explanation for the different modes of inheritance (dominant versus recessive) and the severity of the disease, even though the mutations reside in the same gene (COL7A1) (
Figure 1Illustration of the molecular heterogeneity in the dystrophic forms of EB. The structural organization of the type VII collagen α1(VII) polypeptide deduced from the primary nucleotide sequence of full-length cDNA. The polypeptide consists of a collagenous domain that is flanked by N- and C-terminal noncollagenous domains with modular structures, as indicated on the lower left corner. The arrows indicate positions of distinct mutations disclosed in families with dystrophic forms of EB. The mutations depicted above the α1(VII) collagen polypeptide are recessive, and most of them cause premature termination codons, either as a result of nonsense mutations, insertions, or deletions, or as out-of-frame exon skipping mutations, predicting synthesis of a truncated polypeptide or downregulation of the corresponding mRNA transcript through nonsense-mediated mRNA decay. The mutations depicted below the polypeptide are glycine substitution mutations within the collagenous domain. The majority of these missense mutations cause dominantly inherited dystrophic EB through dominant negative interference. (Modified from
Another example of a condition in which recent progress has provided understanding of the molecular basis of a genodermatosis is PXE, a systemic heritable connective tissue disorder characterized by progressive calcification of elastic structures in the skin, the eyes, and the cardiovascular system. Certain clinical features, including delayed onset of the clinical manifestations and considerable intra- and interfamilial phenotypic variability, have been puzzling (
). Adding to the complexity of PXE is the fact that both autosomal recessive and autosomal dominant inheritance patterns have been reported, and in many cases PXE is sporadic without family history, the precise mode of inheritance thus being unclear (
). Furthermore, the genetic complexity has been compounded by suggestions that obligate heterozygous carriers in families with autosomal recessive forms of PXE may show minimal manifestations of the disease (
). Nevertheless, the involvement of the elastic structures in the skin, the eyes, and the cardiovascular system, and the accumulation of a number of extracellular matrix components, including fibronectin and vitronectin as well as various proteoglycan/glycosaminoglycan complexes, in the lesional areas of skin in association with elastic fibers, have suggested that PXE is a primary heritable connective tissue disease. In fact, it has been considered as a prototype of such conditions with the primary involvement of elastic fibers (
The underlying molecular defect in PXE has remained unknown until recently. Initial observations indicating pathology in the elastic fibers suggested that elastin and elastin-associated microfibrillar proteins could serve as candidate gene/protein systems in PXE. Subsequently, however, the genes encoding elastin as well as elastin-associated proteins, such as fibrillins 1 and 2 and lysyl oxidase on chromosomes 15 and 5, were excluded by genetic linkage analysis. Subsequent positional cloning approaches allowed mapping of the PXE gene to the short arm of chromosome 16, and the critical interval was further narrowed to ≈500 kb within the chromosomal region 16p13.1 (
). Examination of the genome database revealed that this region contained four distinct genes with no apparent relation to the extracellular matrix of connective tissue in general or the elastic fiber system in particular. Two of the genes, ABCC1 and ABCC6, encode proteins, MRP1 and MRP6, respectively, that are members of the multiple drug resistance-associated protein (MRP) family. Another gene, NPIP, was found to encode the nuclear pore interacting protein, whereas the fourth gene, pM5, encodes a protein with unknown function but shares some similarity with the conserved domain within the collagenase family of proteins.
Sequencing of the four candidate genes within the critical PXE interval resulted in identification of pathogenetic mutations in the ABCC6 gene, which encodes MRP6, a member of the ATP-dependent membrane transporter family of proteins (
). Sequence information derived from full-length ABCC6 cDNA predicts that MRP6 has three transmembrane spanning domains and two intracellular nucleotide-binding folds (NBF1 and NBF2) (Figure 2). The NBF domains contain conserved Walker motifs, critical for ATP binding and for the function of the protein as a transmembrane transporter. Mutation detection strategies have identified a number of single-base pair substitutions, resulting in missense or nonsense mutations, as well as several small insertions and deletions or large deletions in the ABCC6 gene (Figure 2). The majority of the mutations reside in the carboxyl-terminal half of the MRP6 polypeptide, affecting critical arginine residues or other conserved amino acids. Furthermore, premature termination codon mutations or large deletions frequently lead to elimination of the third transmembrane domain and the second nucleotide-binding fold. Finally, gene conversion between ABCC6 and one of its pseudogenes has been suggested as a pathogenetic event in some families with PXE (
A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: Implications for mutation analysis in pseudoxanthoma elasticum.
). The mutations in ABCC6 are present either in a homozygous or in a compound heterozygous state in the affected individuals, whereas heterozygous carriers are clinically unaffected, consistent with autosomal recessive inheritance pattern. In fact, no molecular evidence for autosomal dominant mode of inheritance has been demonstrated as yet, although some of the heterozygous carriers may demonstrate minimal manifestations of the disease (
). Also, in some families, the proposed autosomal dominant mode of inheritance could be explained by a pseudodominant family pedigree due to consanguinity in the family (
Figure 2Schematic representation of MRP6, a putative transporter protein, altered by mutations in PXE. As shown, MRP6 consists of three transmembrane domains with five, six, and six transmembrane spanning segments, respectively. The protein is predicted to have two intracellular nucleotide binding folds (NBF1 and NBF2). The repertoire of mutations within MRP6, as recently published (
A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: Implications for mutation analysis in pseudoxanthoma elasticum.
Compound heterozygosity for a recurrent 16.5 kb Alu-mediated deletion mutation and single-base substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.
;Pulkkinen et al, 2001) is illustrated by arrows pointing to the regions affected by mutations. The majority of the mutations replace critical amino acid residues within the intracellular domains of MRP6 or cause premature termination of translation. Note the presence of large deletion mutations depicted on the top of the figure. Two recurrent mutations, R1141X and del exons 23–29, are in bold. EC, extracellular; IC, intracellular.
A surprising finding in the context of clinical manifestations of PXE is the fact that ABCC6/MRP6 is expressed predominantly, if not exclusively, in the liver and the kidneys. The biological function of MRP6 is currently unknown, but there is strong sequence homology with other members of the MRP family, particularly with MRP1, the prototypic protein within the family, which functions as an efflux pump for amphipathic and glutathione conjugates. These observations suggest that MRP6 is a metabolic pump expressed in the liver and the kidneys, and PXE could potentially be considered as a metabolic disorder, rather than being a primary connective tissue disease (
). One could speculate that when MRP6 as a cellular transporter is genetically altered to be nonfunctional, accumulation of yet to be identified compounds in the circulation could take place. Such compounds could have affinity for elastic fibers and calcium and potentially lead to progressive calcification of elastic structures in the affected organs, resulting in progressive degeneration and pathology in the target tissues.
The Impact of Molecular Genetics on Patient Care
The progress made in understanding EB, PXE, and other genodermatoses raises a number of critical questions: What are the benefits of this progress in basic research to the patients and their families? How can we translate this basic information to improved patient care? Is there anything that the practicing dermatologist can convey to the benefit of the patients concerning their disease and its molecular basis? In other words, what is the impact of molecular genetics on the patient care? Collectively, significant benefits are already accruing from the basic research on heritable blistering skin diseases, and expansion of the research database will provide additional insights into the clinical perspective of these conditions.
For example, the immediate benefits for EB have already materialized through improved, molecularly based diagnosis with refined classification, which allows better prognostication regarding the severity and the natural progress of the disease. An example is provided by the junctional form of EB (JEB), which has been traditionally divided, on the basis of the clinical outcome, to two broad categories: (i) the Herlitz variant of JEB that is usually lethal during the first few months of life; and (ii) the non-Herlitz variant that demonstrates persistent blistering tendency throughout the life, without significantly compromising the overall lifespan. Molecular analysis of the JEB patients' DNA has revealed that those with the Herlitz variant harbor, as a general rule, a premature termination codon mutation, i.e., a gene defect that predicts synthesis of a truncated and nonfunctional polypeptide, in both alleles of any of the three genes encoding laminin 5 subunits (LAMA3, LAMB3, and LAMC2) (
). In contrast, patients with the non-Herlitz variants harbor frequently a missense mutation, i.e., an amino acid substitution-causing mutation, in one or both alleles of the corresponding genes. Thus, analysis of DNA from a newborn with clinical, histopathologic, and ultrastructural evidence of JEB allows general predictions as to whether the disease is the severe Herlitz (lethal) variant, or whether the individual is expected to have relatively mild non-Herlitz JEB with a normal lifespan (
Another example of the impact of molecular genetics relates to genetic counseling of families at risk for recurrence of the disease in the same and subsequent generations. An example is provided by a “sporadic” patient with relatively mild DEB with no family history of the disease, and specifically, both parents being clinically normal. The disease in the affected individual could result either from a new (de novo) dominant mutation in one allele of the type VII collagen gene, or the disease could be a mild (mitis) recessive DEB due to mutations in both type VII collagen alleles, inherited separately from each parent. These two possibilities are indistinguishable by clinical examination, as well as by histopathologic, immunohistochemical, and ultrastructural analysis (
). This diagnostic dilemma can be solved, however, by analysis of mutations in the DNA from the affected individual and his/her parents. Specifically, presence of a single mutation in the proband, in the absence of the corresponding mutation in the parents' DNA isolated from peripheral blood, indicates a de novo dominant mutation. In contrast, identification of two mutant alleles in the proband's DNA and demonstration of their presence in the respective parents signifies mitis recessive DEB. The implications are, of course, that the risk of an affected individual in the case of de novo dominant DEB of having an affected child is one in two, or 50%, whereas the risk of the individual with recessive DEB having an affected offspring is very low, reflecting the relatively low carrier frequency of EB (
). At the same time, the risk for the parents of the patient with a de novo dominant mutation of having another affected child is relatively low, whereas the risk for the parents of the patient with a recessive DEB having another affected offspring is one in four, or 25%.
Prenatal Testing, Preimplantation Genetic Diagnosis, and Gene Therapy
A consequence of the identification of specific mutations in genodermatoses has been the development of DNA-based prenatal testing for families at risk for recurrence of severe forms of the disease. Such testing can be performed from a chorionic villus sample as early as the tenth week of gestation or from early amniocentesis performed at the twelfth week. In fact, prenatal testing has already been established for EB and is readily available for the severe forms of recessive DEB and for the Herlitz type of JEB during the first trimester of pregnancy (
Prenatal diagnosis of recessive dystrophic epidermolysis bullosa in ten families by mutation and haplotype analysis in type VII collagen gene (COL7A1).
). DNA-based analysis has essentially replaced the previously employed fetal skin biopsy, which is performed late during the second trimester, as a prenatal diagnostic tool for EB.
An extension of DNA-based prenatal testing is the development of preimplantation genetic diagnosis (PGD), which is performed in conjunction with in vitro fertilization (
). In this procedure, the fertilized embryos are allowed to grow in vitro to the eight-cell stage level, at which time one cell is removed for mutation analysis. Subsequently, embryos lacking the mutation are implanted into the uterus to establish pregnancy, as routinely done as part of in vitro fertilization protocol, therefore excluding the recurrence of the disease in the family. Thus, couples with a child previously affected with EB, or any other severe genodermatosis in which the molecular basis is known, can now initiate the next pregnancy by knowing that there are ways to find out the genotype of the fetus at the early stages of pregnancy through DNA-based prenatal testing or even before the pregnancy is established by applying PGD.
Finally, it is evident that identification of the underlying molecular defects in genodermatoses is a prerequisite for development of successful therapies in the future. In particular, development of gene therapy approaches requires precise knowledge of the mutations in the affected genes and their consequences at the mRNA and protein levels (
). Although successful application of gene therapy for treatment of EB may still be several years away, rapid development of new technologies or promising breakthroughs could lead to durable gene therapy for these devastating skin diseases in the future.
Future Prospects: Complex Disorders and Genetic Susceptibility
As illustrated above, significant progress has been made towards understanding the molecular basis of a large number of genodermatoses, and in fact, the majority of the single gene disorders may have been mapped to distinct genetic loci and the underlying mutated genes have been identified. Nevertheless, the molecular basis of a number of Mendelian disorders still awaits clarification, and it is becoming increasingly evident that a number of disorders can be caused by defects in different genes with resulting phenocopies or closely resembling phenotypes (Table I). An example of such molecular diversity is Vohwinkel's syndrome, characterized by mutilating keratoderma with pseudoainhum, ichthyosiform erythroderma, and deafness. Our original attempts to clarify the genetic basis of Vohwinkel's syndrome in a family with keratoderma and erythroderma resulted in identification of mutations in the gene encoding loricrin, a cornified envelope protein expressed in the epidermis (
). Subsequently, however, examination of families with classic, more complete forms of Vohwinkel's disease manifesting with deafness, led to identification of mutations in the GJB2 gene encoding connexin 26, a cell–cell communication protein (
). As another example, different variants of X-linked anhidrotic ectodermal dysplasia have been shown to result from mutations, in addition to ED1, in the IKBKG gene that encodes NEMO, a subunit of the IκB kinase complex (Table I). At the same time, incontinentia pigmenti, a complex X-linked dominant disorder, is also due to mutations in the IKBKG gene (
). The dramatic phenotypic differences in X-linked ectodermal dysplasias, either with immunodeficiency (EDA-ID) or together with osteopetrosis and lymphedema (OL-EDA-ID), and in incontinentia pigmenti can be explained by the consequences of the mutations within the same gene. Specifically, loss of function mutations in IKBKG, which abolish NFκB signaling, result in incontinentia pigmenti (
). Furthermore, EDA variants without immune deficiency, can be caused by mutations in two different genes. The X-linked variants are due to mutations in the ED1 gene encoding ectodysplacin A, whereas the autosomal variants with essentially identical phenotypes are due to mutations in the ectodysplacin A receptor gene (DL) (
). Both of these gene products participate in NFκB signaling. Thus, further expansion of the molecular basis of single gene disorders, with extended mutation databases towards refinement of genotype/phenotype correlations, is still required for understanding of a number of single gene disorders.
At the same time, the molecular diagnostics of genodermatoses is expanding to include complex genetic disorders towards identification of susceptibility genes (Table III). A prime example of such conditions is psoriasis, which is clearly known to have a genetic contribution with a major susceptibility locus residing on chromosome 6 in association with the HLA locus. In fact, a number of candidate genes have been recently identified, and evidence in support of certain genes or in favor of exclusion of the corresponding genes is rapidly appearing in the literature (see, for example,
). Further examples of such conditions are autoimmune disorders, such as systemic lupus erythematosus and vitiligo, for which a shared genetic susceptibility locus has been recently linked to chromosome 17p13 (
Another example of a relatively common, complex disorder is atopic dermatitis, and the loci influencing atopy have been localized to a number of chromosomal regions, including chromosome 5q31. This region includes SPINK5, which has recently been identified to cause Netherton syndrome, a rare recessive skin disorder in which atopy is a universal component (
The spectrum of pathogenic mutations in SPINK 5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis.
). SPINK5 encodes a complex serine protease inhibitor (LEKTI), which is expressed in epithelial and mucosal surfaces as well as in the thymus. A number of coding polymorphisms in the SPINK5 gene have been demonstrated, and it was discovered that Glu420Lys shows significant association with atopic dermatitis in two independent panels of families (
). These results implicate a previously unrecognized pathway for the manifestations of atopic dermatitis, and they potentially provide means to interfere with the development of this condition by pharmacologic means. Collectively, these developments herald the extension of molecular genetics to more common cutaneous disorders for which the molecular basis and the pathomechanisms will be the subject of intense research over the next decade.
ACKNOWLEDGMENTS
The authors thank Carol Kelly for helpful assistance in preparation of this manuscript. The original studies by the authors were supported by the National Institutes of Health and the Dermatology Foundation.
References
Ahmad W.
Panteleyev A.A.
Christiano A.M.
The molecular basis of congenital atrichia in humans and mice: mutations in the hairless gene.
Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase.
in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects 2nd edn. New York,
Wiley-Liss2002: 687-725
A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: Implications for mutation analysis in pseudoxanthoma elasticum.
Prenatal diagnosis of recessive dystrophic epidermolysis bullosa in ten families by mutation and haplotype analysis in type VII collagen gene (COL7A1).
Revised classification system for inherited epidermolysis bullosa. Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa.
A homozygous insertion-deletion in the type VII collagen gene (COL7A1) predicting a truncated protein in the Hallopeau-Siemens form of recessive dystrophic epidermolysis bullosa.
Lipoxygenase-3 (ALOXE3) and 12 (R) -lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.
Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase: identification of the first molecular lesion causing Farber disease.
Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).
Molecular basis for the progeroid variant of Ehlers–Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene.
Compound heterozygosity for a recurrent 16.5 kb Alu-mediated deletion mutation and single-base substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.
The spectrum of pathogenic mutations in SPINK 5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis.
in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects 2nd edn. New York,
Wiley-Liss2002: 431-523
Epidermolysis bullosa. The disease of the cutaneous basement membrane zone.
in: Scriver C.R. Beaudet A. Valle D. Sly W.S. Vogelstein B. Kintler K.W. Childs B. The Metabolic and Molecular Bases of Inherited Disease 8th edn. New York,
McGraw-Hill2001: 5655-5674
Heritable diseases affecting the elastic tissues. Cutis laxa, pseudoxanthoma elasticum and related disorders.
in: Rimoin D.L. Connor J.M. Pyeritz R. Korf B.R. Emery & Rimoin's Principles, Practice of Medical Genetics. Vol, 3. New York,
Churchill Livingstone2002: 4044-4070
52918-7&id=gr1.jpg){kind=link}
52918-7&id=gr2.jpg){kind=link}