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.