Kindler syndrome: a focal adhesion genodermatosis

Clinics in Dermatology, 2001

Journal of Investigative Dermatology, 2004

2010

Chapter 9 fragility, whereas the, for EI characteristic, ichthyotic scaling and neonatal erythroderma were lacking. Of note, the clinical features resembled the phenotype of the patients with the one other, previously reported K1 L12 domain mutation. 8 With transfection studies we have shown that both the novel and the previously reported K1 L12 mutation cause keratin aggregations in vitro. This effect was aggravated upon application of a hypo-osmotic stress stimulus to the cells. In general, the functions of the linker domains of IFs are not well known. The results of the transfection studies performed in chapter 4 indicate that the L12 domain is involved in normal keratin assembly and stress resistance. The K1 L12 domain mutations cause mild phenotypes that might be missed because of the lack of resemblance to classical EI. The observation of unexplainable palmoplantar keratoderma in combination with mild skin fragility, blistering and/or peeling-skin like features should raise the suspicion of EI due to K1 linker domain mutations, especially when suprabasal epidermolysis and/or keratin aggregation is observed in ultrastructural analysis of patient's skin. Notably, in view of this mild blistering phenotype, EI could also be considered as a form of suprabasal EBS, although this was not acknowledged in the latest EB consensus, mainly because EI is generally thought of as an ichthyosiform, scaling disorder. Recently, we have discovered a novel, dominantly inherited missense mutation in the K10 L12 domain in a family with an even milder, more acral-peeling-skin-syndrome-like phenotype (unpublished). In general, mutations in the type II keratin K1 are associated with more severe phenotypes than mutations in K10 (type I). Moreover, recessive loss-of-protein expression mutations have been reported for K10, but not for K1. Similarly, in basal keratins only recessive loss-of-protein mutations have been observed for the type I keratin K14, but not for the type II K5. Furthermore, K5-knockout mice show a more severe and earlier lethal phenotype then the K14-knockout mice. 9 All these findings most likely reflect the functional redundancy of keratins. K14 loss can be (partly) compensated for by another basal keratin, K15, and upregulation of the wound-repair keratin K16. Furthermore, K10 mutations can be (partly) compensated for by expression of an additional type I keratin (K9) in palmoplantar skin. 10 On the other hand, patients with K9 mutations have palmoplantar keratoderma, so apparently K10 cannot compensate for K9 mutations. The type I keratins K5 and K1 have no alternative heterodimer partners, and therefore alterations in these proteins may cause more severe phenotypes. Alternatively, functional properties of type I and type II proteins differ. Of note, the phenomenon of functional redundancy of keratins is interesting in the light of therapeutic options for hereditary keratin disorders, as upregulation of other keratins may reduce the detrimental effect of the mutated keratin. Additional transfection studies will reveal whether the novel K10 L12 domain mutation has the same detrimental effect on the keratin cytoskeleton as the K1 L12 mutations in vitro, or perhaps has no notable effect and therefore causes such a mild phenotype. It would be interesting to perform transfections studies with the both the K1 and K10 linker domain mutations, and with helix boundary motif-affecting mutations as well.

Matrix biology : journal of the International Society for Matrix Biology, 2018

Epidermolysis bullosa (EB), a group of heritable skin fragility disorders, is characterized by blistering, erosions and chronic ulcers in the skin and mucous membranes. In some forms, the blistering phenotype is associated with extensive mutilating scarring and development of aggressive squamous cell carcinomas. The skin findings can be associated with extracutaneous manifestations in the ocular as well as gastrointestinal and vesico-urinary tracts. The phenotypic heterogeneity reflects the presence of mutations in as many as 20 different genes expressed in the cutaneous basement membrane zone, and the types and combinations of the mutations and their consequences at the mRNA and protein levels contribute to the spectrum of severity encountered in different subtypes of EB. This overview highlights the molecular genetics of EB based on mutations in the genes encoding type VII and XVII collagens as well as laminin-332. The mutations identified in these protein components of the extrac...

Abstract Epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disorders, is characterized by blistering and erosions with considerable morbidity and mortality. Mutations in as many as 18 distinct genes expressed at the cutaneous basement membrane zone have been shown to be associated with the blistering phenotype, attesting to the role of the corresponding proteins in providing stable association of the epidermis to the dermis through adhesion at the dermo-epidermal basement membrane zone. Thus, different forms of EB have been highly instructive in providing information on the physiological functions of these proteins as integral components of the supramolecular adhesion complexes. In addition, precise information of the underlying genes and distinct mutations in families with EB has been helpful in subclassification of the disease with prognostic implications, as well as for prenatal testing and preimplantation genetic diagnosis. Furthermore, knowledge of the types of mutations is prerequisite for application of allele-specific treatment approaches that have been recently developed, including read-through of premature termination codon mutations and chaperone-facilitated intracellular transport of conformationally altered proteins to proper physiologic subcellular location. Collectively, EB serves as a paradigm of heritable skin diseases in which significant progress has been made in identifying the underlying genetic bases and associated aberrant pathways leading from mutations to the phenotype, thus allowing application of precision medicine for this, currently intractable group of diseases. Keywords Epidermolysis bullosa; heritable blistering diseases; cutaneous basement membrane zone; type VII collagen

2013

Archives of Biochemistry and Biophysics, 2011

Keratins, the major structural protein of all epithelia, are a diverse group of cytoskeletal scaffolding proteins that form intermediate filament networks, providing structural support to keratinocytes that maintain the integrity of the skin. Expression of keratin genes is usually regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Amongst the 54 known functional keratin genes in humans, about 21 different genes including hair and hair follicle-specific keratins have been associated with diverse hereditary disorders. The exact phenotype of each disease mostly reflects the spatial level of expression and types of the mutated keratin genes, the positions of the mutations as well as their consequences at sub-cellular levels. The identification of specific mutations in keratin disorders is the basis of our understanding that lead to reclassification, improved diagnosis with prognostic implications, prenatal testing and genetic counseling in severe cutaneous keratin genodermatoses. A disturbance in cutaneous keratins as a result of mutation(s) in the gene(s) that encode keratin intermediate filaments (KIF) causes keratinocytes and cutaneous tissue fragility, accounting for a large number of genetic disorders in human skin and its appendages. These diseases are characterized by a loss of structural integrity in keratinocytes expressing mutated keratins in vivo, often manifested as keratinocytes fragility (cytolysis), intra-epidermal blistering, hyperkeratosis, and keratin filament aggregation in severely affected tissues. Examples include epidermolysis bullosa simplex (EBS), keratinopathic ichthyosis (KPI), pachyonychia congenital (PC), monilethrix, steatocystoma multiplex and ichthyosis bullosa of Siemens (IBS). These keratins also have been identified to have roles in cell growth, apoptosis, tissue polarity, wound healing and tissue remodeling.

Abstract Introduction: Kindler syndrome (KS) is a complex skin fragility disorder with protean manifestations with considerable morbidity and occasional mortality from cancer development. The characteristic clinical features include blistering, erosions, poikiloderma, atrophy of the skin, photosensitivity and severe involvement of mucous membranes. Ultrastructural findings in the affected skin include tissue cleavage at different, mixed levels at the cutaneous basement membrane zone and reduplication of the dermal-epidermal basement membrane. Areas covered: The molecular basis of this orphan disease, a subtype of epidermolysis bullosa with autosomal recessive inheritance, has been recently elucidated, and there is increased understanding of the pathomechanistic pathways leading to phenotypic manifestations as a result of mutations in FERMT1. This gene encodes kindlin-1, a multi-functional focal adhesion protein with a role in keratinocyte adhesion and proliferation. Expert opinion: Information on the genetic basis of this disorder is helpful for confirming the diagnosis with prognostic implications, and it has formed the basis for prenatal testing and preimplantation genetic diagnosis in families at risk for recurrence. Finally, information on the specific mutations and understanding of the pathomechanistic pathways has formed the basis to develop novel allele-specific treatment approaches for this, currently intractable disorder.

Frontiers in Bioscience, 2012

PubMed, 1995

To explore the relationship between abnormal keratin molecules, 10-nm intermediate filament (IF) organization, and epidermal fragility and blistering, we sought to determine the functional consequences of homozygosity for a dominant keratin defect. We describe a family with an autosomal dominant skin-blistering disorder, epidermolysis bullosa simplex, Koebner subtype (EBS-K), that has a novel point mutation, occurring in the keratin 5 gene (KRT5), that predicts the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N). Unlike previous heterozygous mutations located within the initial segment of domain 1A of keratin molecules, K173N heterozygosity did not result in severe disease or clumping of keratin filaments. One family member was found to be homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. Despite a lack of normal keratin 5 molecules, and an effective doubling of abnormal molecules, available for heterodimerization with keratin 14 during IF formation, there were no significant differences in the clinical severity or the ultrastructural organization of the keratin IF cytoskeleton of the homozygous individual. These data demonstrate that the K173N mutation behaves as a fully dominant allele and indicate that a limited number of abnormal keratin molecules are sufficient to impair cytoskeletal function and elicit epidermal fragility and blistering.