Mutations in the Desmoglein 4 Gene Underlie Localized Autosomal Recessive Hypotrichosis with Monilethrix Hairs and Congenital Scalp Erosions

Schaffer, Julie V.; Bazzi, Hisham; Vitebsky, Anna; Witkiewicz, Agnieszka K.; Kovich, Olympia I; Kamino, Hideko; Shapiro, Lawrence; Amin, Snehal P.; Orlow, Seth J.; Christiano, Angela M.

doi:10.1038/sj.jid.5700237

Cited by 69 publications

(75 citation statements)

References 31 publications

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“…Interestingly, the clinical features of patients harboring this mutation are a focal nonstriated form of PPK associated with discrete keratinization at sites exposed to mechanical trauma, such as the knees, ankles, and finger knuckles, and with mild nail dystrophy. In addition, Keren et al 109 reported a family affected with a diffuse nonstriated form of PPK that harbored a recurrent mutation in Dsg1, previously associated with cases of SPPK. These studies reveal that mutations in Dsg1 are not exclusively associated with SPPK.…”

Section: Desmogleinmentioning

confidence: 99%

Desmosome assembly, homeostasis, and desmosomal disease

Cirillo¹

2016

CHC

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Cell-cell adhesion is involved in all aspects of tissue behavior in multicellular organisms, from tissue morphogenesis (regulation of cell shape, apoptosis, cell movement, and development of complex structures) to aging and disease. A major player in the dynamic regulation of intercellular contacts is the desmosome. Knowledge of the desmosome has evolved over 150 years from the notion of a static, punctuate, adhesive barrier structure to one of the finely tuned multifunctional complexes involved in the regulation of numerous and diverse aspects of keratinocyte physiology and disease. In this context, nondesmosomal regulatory molecules have been acquiring increasing importance in the study of desmosome homeostasis and have become part of the extended desmosomal interactome named "desmo-adhesome". Among these associated molecules, kinases are the prominent regulators of both desmosome remodeling and acquisition of hyperadhesion, two novel concepts in cell-cell adhesion. Spatiotemporal changes in the expression and regulation of desmosomal proteins also underlie a number of genetic, infectious, autoimmune, and malignant conditions. In addition to offering a systems-level view of the molecular composition of desmosomes, we also discuss the mechanisms that regulate, and disrupt, desmosome homeostasis.

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Section: Desmogleinmentioning

confidence: 99%

Desmosome assembly, homeostasis, and desmosomal disease

Cirillo¹

2016

CHC

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“…This amino acid substitution is located within a highly conserved motif (RAL) corresponding to the HAV region of classical cadherins, a domain that is important in cell-cell adhesion. In 2006, further missense, splice site, frameshift and nonsense mutations in the DSG4 gene were reported [85][86][87]. However, the phenotype in these cases was described as autosomal recessive monilethrix.…”

Section: Desmoglein 4 Mutations Cause Hair Abnormalitiesmentioning

confidence: 99%

Diseases of epidermal keratins and their linker proteins

Uitto

Richard

McGrath³

2007

Experimental Cell Research

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Epidermal keratins, a diverse group of structural proteins, form intermediate filament networks responsible for the structural integrity of keratinocytes. The networks extend from the nucleus of the epidermal cells to the plasma membrane where the keratins attach to linker proteins which are part of desmosomal and hemidesmosomal attachment complexes. The expression of specific keratin genes is regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Progress in molecular characterization of the epidermal keratins and their linker proteins has formed the basis to identify mutations which are associated with distinct cutaneous manifestations in patients with genodermatoses. The precise phenotype of each disease apparently reflects the spatial level of expression of the mutated genes, as well as the types and positions of the mutations and their consequences at mRNA and protein levels. Identification of specific mutations in keratinization disorders has provided the basis for improved diagnosis and subclassification with prognostic implications and has formed the platform for prenatal testing and preimplantation genetic diagnosis. Finally, precise knowledge of the mutations is a prerequisite for development of gene therapy approaches to counteract, and potentially cure, these often devastating and currently intractable diseases. KeywordsEpidermal keratins; intermediate filaments; epidermal differentiation; hemidesmosomes; desmosomes; genodermatoses; skin fragility; epidermolysis bullosa; epidermolytic hyperkeratosis; ichthyosis Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. BIOLOGY OF EPIDERMAL KERATINSKeratins NIH Public Access Author ManuscriptExp Cell Res. Author manuscript; available in PMC 2008 November 4. Published in final edited form as:Exp Cell Res. 2007 June 10; 313(10): 1995-2009. doi:10.1016/j.yexcr.2007.03.029. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dimensional and highly dynamic cytoskeleton spanning between the nucleus and the cell membrane, where they are anchored by interactions with desmosomal and hemidesmosomal linker proteins (Fig. 1). This organization provides both structural stability and flexibility, and ensures the mechanical integrity of different epithelial tissues. Keratins are expressed as obligate heterodimers of acidic (type I) and basic (type II) proteins, which assemble, through a multi-step process, into intermediate filaments (Fig. 2). The genes encoding type I and type II keratins cluster on chromosomal regions 17q12-q21 and 12q11-q13, respectively. Keratin ...

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“…More recently, DSG4 gene mutations were found to be associated with human monilethrix hairs (Shimomura et al, 2006;Amagai, 2010). These studies convincingly demonstrate that DSG4 plays an important role in regulating the proliferation and differentiation of hair follicles in mammals (Schaffer et al, 2006;El-Amraoui and Petit, 2010). Although our knowledge about the sheep DSG4 gene remains limited, some DNA sequences of sheep that are homologous to this gene in other organisms are available in the GenBank.…”

Section: Introductionmentioning

confidence: 97%

Identification of complete linkage disequilibrium in the DSG4 gene and its association with wool length and crimp in Chinese indigenous sheep

Ling¹,

Xiang²,

Zhang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The desmoglein 4 (DSG4) gene is a potential candidate in the search for genes that may affect wool traits, because of its function. This study aimed to screen for polymorphisms in partial exon 16 and 3ꞌUTR of the sheep desmoglein 4 DSG4 gene, and to test its possible association with wool length and crimp associated with fur. Overall, 326 sheep were scanned via single-strand conformational polymorphism assay, through three pairs of primers. The breeds included Tan, Han, and TanxHan from China, Polled Dorset from Australia, and Suffolk from Britain genotypes AA, BB, and AB for primer2 and genotypes DD, EE, and DE for primer3 were detected in native breeds. Six SNPs and 3-bp insertion/deletions were found in exon 16, of which 4 lead to amino acid substitutions. In addition, 1 SNP was found in 3ꞌUTR. The DSG4 genotype was found to be strongly associated with all wool traits that were considered in this study (P < 0.01). Sheep with the genotype MM had a higher least square mean compared to sheep with the genotype WW or WM with respect to birth scapular wool length (P < 0.01), crimp number of birth scapular wool crimp (P < 0.01), crimp number of weaning scapular wool crimp (P < 0.01), and crimp number of weaning rump wool crimp (P < 0.01, P < 0.05). In conclusion, our study is the first to demonstrate that the DSG4 gene may be a candidate, or major gene, which influences important wool traits.

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Mutations in the Desmoglein 4 Gene Underlie Localized Autosomal Recessive Hypotrichosis with Monilethrix Hairs and Congenital Scalp Erosions

Cited by 69 publications

References 31 publications

Desmosome assembly, homeostasis, and desmosomal disease

Desmosome assembly, homeostasis, and desmosomal disease

Diseases of epidermal keratins and their linker proteins

Identification of complete linkage disequilibrium in the DSG4 gene and its association with wool length and crimp in Chinese indigenous sheep

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