Cell Junctions -- Desmosomal Mutations

Desmosomal Mutations in Humans
Component Chromosome References PubMed Search (by days old)	Mutation	Result of Mutation	Defects	Conclusions
Desmoplakin 6P24 Armstrong DK Whittock NV	Heterozygous C>T transition in exon 4 Q331X Heterozygous G > A transition at the splice site of intron 7 (939 + 1 G>A) Dominant	PTC in the region encoding the N-terminal domain. Retention of intron7. PTC in region encoding the N-terminal domain. Null alleles Haploinsufficiency	Striate palmoplantar keratodema (linear pattern of skin thickening on fingers and palms and in islands on soles) in response to poor cell-cell contact. Desmosomes lack inner plaques and fail to bind keratins	Haploinsufficiency Dosage of desmoplakin is critical in maintaining epidermal integrity in sites exposed to intense repetitive mechanical stress. Desmoplakin is required for keratin filament association
Desmoplakin 6P24 Norgett EE	Homozygous 7901delG Recessive	PTC 18 amino acids downstream results in truncation of the C-terminal domain.	Generalized striate palmoplantar keratoderma Woolly hair Dilated left ventricular cardio-myopathy resulting in heart failure during teenage years. Poor cell-cell contact and perinuclear localization of keratin	DP C-terminal domain is essential for attachment of several types of intermediate filaments to desmosomes. This cytoskeletal anchorage is crucial for heart and skin function. DP C-terminal domain is not required for tissue architecture during development as this mutation shows no embryonic lethality.
Plakoglobin 17q21 McKoy G	Homozygous 2 base pair deletion in plakoglobin gene. Recessive	Frameshift leading to addition of ten novel amino acids. PTC results in truncation of the majority of the C-terminal domain.	-Naxos Disease Palmoplantar Keratoderma Woolly hair Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), that causes arrhythmia, heart failure, and sudden death.	The plakoglobin C-terminal domain is essential for the correct structure and function of heart, skin and hair either by its role in desmosomes or through a signaling function.
Plakoglobin 17q21 Aberle	R142H low frequency polymorphism			The gene for plakoglobin lies next to BRCA1 and is subject to LOH in breast and ovarian cancer. The polymorphism segregates with haplotypes associated with predisposition to breast cancer.
Plakophilin 1 1q31 1. McGrath 2.McGrath 3. Whittock	Recessive 1. Compound-het: Q304X 2. Compound-het: T213G=Y71X + splice site mutation 203delG. 3.Homozygous intron 6 splice site mutation: 1233 A-->T deleting exon 7. PTC 154bp in exon 8	Homozygous Null alleles. Mutations ocurr within the N-terminal intermediate filament-binding domainand delete the arm repeats which bind to Dsc	Hypohidrotic ectodermal dysplasia: Defective growth of hair, which is sparse. short & fragile. Thickened dystrophic nails. Reduced sweating. Trauma-induced skin fragility & blisters. Hyperkeratotic palms & soles. Poorly formed desmosomes with altered desmoplakin localization and reduced keratin binding	PKP is a significant accessory desmosomal plaque protein that reinforces keratin association. Defects may be explained by the relatively restricted tissue expression pattern of PKP in skin hair sweat glands
Desmoglein 1 18q12.1 Rickman L	- G>A transition in the 3-prime splice site of intron 2 Dominant	In frame splicing of exon 2 to exon 4, removing exon 3, which encodes part of the prosequence and part of EC1 the first extracellular domain. Haploinsufficiency or dominant negative.	Striate Palmoplantar Keratoderma Retention of 5 aa of the prosequence and deletion of the first 23 aa of EC1comprising the first and second beta-strands and intervening loop containing part of the first Ca2+-binding site is likely to compromise lateral and adhesive dimer formation.	The effects of this mutation demonstrate the importance of Dsg1 for desmosomal function, however the mechanism is not presently clear. Either Dsg1 is not produced and the phenotype reflects haploinsufficincy, or, partial deletion of EC1 compromises Dsg1 dimerization & adhesive function, or, Dsg1 is retained in the endoplasmic reticulum and traps plaque proteins bound to its C-terminal domain.