Human Molecular Genetics, Vol 5, 231-237, Copyright © 1996 by Oxford University Press
S Kivirikko, JA McGrath, L Pulkkinen, J Uitto and AM Christiano
The Herlitz type of junctional epidermolysis bullosa (H-JEB) is a severe
blistering disease affecting the skin and mucous membranes, and laminin 5
has been implicated as the candidate gene/protein system for most patients
with H-JEB. In this study, we have examined a cohort of 14 families with
H-JEB for mutations in the LAMB3 gene. Premature termination codon
mutations were delineated in both alleles of each proband in all pedigrees.
Interestingly, two recurrent mutations, R42X and R635X, were noted in over
50% of the mutant LAMB3 alleles. These nonsense mutations occurred at CpG
dinucleotide sequences, suggesting hypermutability of 5-methylcytosine to
thymine. Additional evidence suggested that R42X and R635X represent
mutational hotspots. First, the inheritance of R635X in a homozygous
individual on two different genetic backgrounds was demonstrated by
haplotype analysis. Furthermore, in one family, R42X was shown to be
inherited on the maternal allele which lacked this mutation, suggesting
that it arose as a result of maternal germline mutation. Elucidation of
these two hotspot mutations will facilitate screening of additional JEB
patients for the underlying mutations.
ARTICLES
Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa
Department of Dermatology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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