Disease relevance of DSG4

• A mutation in DSG1 gene causes striate palmoplantar keratoderma and a mutation in DSG4 gene causes inherited hypotrichosis [1].
• A subset of patients with pemphigus have Dsg1/Dsg4 crossreacting IgG autoantibodies [1].
• The data available on the prognosis of the intraventricular conduction disturbances--left and right bundle branch block (LBBB, RBBB) and left anterior and posterior hemiblock (LAH, LPH)--are uneven [2].
• Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency [3].
• In contrast, the LAH peptides were highly active against P. aeruginosa in an acidic environment, as is found in the epithelial-lining fluid of cystic fibrosis patients [4].

High impact information on DSG4

• We also show that DSG4 is an autoantigen in pemphigus vulgaris [5].
• Conversely, the removal of anti-Dsg4 IgG from pemphigus sera reduced the immunoreactivity against Dsg1 only 13.8% +/- 8.8% (n = 23) and did not affect its ability to induce blisters in neonatal mice [6].
• Desmogleins (Dsg) are transmembrane glycoproteins of the desmosome that allow a cell-cell adhesion between keratinocytes and comprise four different isoforms (Dsg1 to Dsg4) [7].
• Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful [3].
• Here we present the observation that mutations in the DSG4 gene can cause monilethrix-like congenital hypotrichosis [8].

Chemical compound and disease context of DSG4

• At neutral pH, the LAH peptides were active against both methicillin-resistant and -sensitive Staphylococcus aureus strains but ineffective against Pseudomonas aeruginosa [4].

Biological context of DSG4

• Analysis of the exon/intron organization of the human desmoglein 4 gene (DSG4) demonstrates that it is composed of 16 exons spanning approximately 37 kb of 18q12 and is situated between DSG1 and DSG3 [9].
• The highly specific expression pattern of DSG4 in the human hair follicle, combined with the phenotype of rodent models and human patients with desmoglein 4 mutations, underscores the importance of this adhesion molecule in the integrity of the hair shaft [10].
• The human desmoglein 4 cDNA (3.6 kb) contains an open reading frame of 3120 bp that encodes a precursor protein of 1040 amino acids [9].
• Novel compound heterozygous DSG4 mutations, including a splice-site mutation and a missense mutation that disrupts a conserved calcium-binding site in the extracellular (EC)2-EC3 interface, were found to underlie the disease in this family [11].
• Transfection activity of Gal-alpha-CDE conjugate (DSG 4) was insensitive to the existence of competitors (asialofetuin and galactose) and serum [12].

Anatomical context of DSG4

• In the human hair follicle, DSG4 is expressed specifically in the hair shaft cortex, the lower hair cuticle, and the upper inner root sheath (IRS) cuticle [10].
• We have demonstrated using RT-PCR on multiple tissue cDNA samples that desmoglein 4 has very specific tissue expression in salivary gland, testis, prostate, and skin [9].
• In human, Dsg4 was detected primarily in the granular and cornified cell layers of the epidermis, while present throughout all differentiated layers of the oral mucosa and palm, and in the matrix cells of anagen hair bulb [13].
• Using a green fluorescent protein-tagged version of mouse or rat desmoglein 4 protein (Dsg4) and immuno-electron microscopy, we demonstrate that Dsg4 localizes to desmosomes both in vitro and in vivo [10].
• Eleven out of 12 cases (91.7%) in Group 1 had severe lesions at LBBa or the His bundle and we propose that LAD in excess of -30 degrees is a good criterion in hypertension for LAH [14].

Associations of DSG4 with chemical compounds

• A preparation of heparin was separated by affinity chromatography into two fractions: one of high ( HAH ) and the other of low (LAH) affinity to antithrombin III [15].
• The radical-mediated, intermolecular bridgehead C-C bond formation of the versatile bridged lactones 10 with acrylonitrile followed by LAH reduction of the adduct 13 intriguingly leads to the formation of novel spirolactam building blocks 1 [16].
• This efficient approach has been illustrated by the synthesis of 1-deoxymannojirimycin including a stereoselective reduction with LAH and a Tamao-Fleming oxidation of a C-SiMe(2)Ph bond [17].
• Reaction with the lithium enolate of ethyl diethylphosphonoacetate, and then LAH reduction, converts 1 to 4,4-difluorogeraniol 11, with complete stereoselectivity [18].
• The conversion of these vicinal diols to the corresponding cyclic sulfate, regio-, stereoselective nucleophilic ring opening by sodium azide, and LAH reduction afforded amino heptitols 7a,b that were converted to azepane 1c,d and nojirimycin analogues 2c,d [19].

Analytical, diagnostic and therapeutic context of DSG4

• In addition, various mutations in the Dsg4 gene have been identified in animal models of hypotrichosis that share a characteristic phenotype called "lanceolate hair". To date, the features of the hair-shaft anomaly in patients with LAH have not been well described [8].
• The critical factor in a bad late prognosis in patients with ECG evidence of RBBB and LAH may be with ECG evidence of RBBB and LAH may be the history of transient postoperative CHB [20].
• This report describes the occurrence of Mobitz type II AV block during surgery under general anesthesia in a patient with apparently uncomplicated right bundle branch and left anterior fascicular block (RBBB and LAH) [21].

References