Homozygous mutations in the 5' region of the JUP gene result in cutaneous disease but normal heart development in children.
Desmosomes are intercellular adhesive junctions and attachment sites for the intermediate filament (IF) cytoskeleton, prominent in tissues subject to high levels of mechanical stress such as the epidermis and heart. The obligate desmosomal constituent, plakoglobin (PG), is involved in coupling transmembrane desmosomal components with IFs. PG also contributes to intercellular adhesion through adherens junctions and has additional signaling roles. To date, two mutations in the gene encoding PG, JUP, have been described, and in both instances, patients harboring pathogenic mutations suffered from arrhythmogenic right ventricular cardiomyopathy with or without skin abnormalities. We describe homozygous nonsense mutation, p.S24X, and homozygous splice site mutation, c.468G>A, in the JUP gene that results in skin fragility, diffuse palmoplantar keratoderma, and woolly hair with no symptoms of cardiomyopathy. We show barely detectable levels of PG immunostaining in skin sections from patients harboring these mutations and show that an alternative AUG codon in p.S24X mRNA translates a 42-amino-acid N-terminal truncation. We conclude that PG is required for correct maintenance of skin integrity, and the absence of heart phenotype in patients suggests that aberrant PG expression does not compromise normal human heart development in children. Our findings provide new insight into the distinct roles that PG has in the epidermis and heart.
Cabral
Rita M
RM
Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, University of London, London, UK.
Liu
Lu
L
Hogan
Carol
C
Dopping-Hepenstal
Patricia J C
PJ
Winik
Beatriz C
BC
Asial
Raúl A
RA
Dobson
Richard
R
Mein
Charles A
CA
Baselaga
Patricia A
PA
Mellerio
Jemima E
JE
Nanda
Arti
A
Boente
Maria del Carmen
Mdel C
Kelsell
David P
DP
McGrath
John A
JA
South
Andrew P
AP
D001706:Biopsy; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics* / Q000502:physiology; D005260:Female; D006321:Heart / Q000254:growth & development* / Q000502:physiology; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D021141:Nucleic Acid Amplification Techniques; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D012873:Skin Diseases, Genetic / Q000235:genetics* / Q000503:physiopathology; D051185:gamma Catenin
D018389:Codon, Nonsense; D018076:DNA, Complementary; D051180:Desmoplakins; C495292:JUP protein, human; D022821:RNA Splice Sites; D012333:RNA, Messenger; D051185:gamma Catenin