PREDOMINANCE OF THE RECURRENT MUTATION R635X IN THE LAMB3 GENE IN EUROPEAN PATIENTS WITH HERLITZ JUNCTIONAL EPIDERMOLYSIS-BULLOSA HAS IMPLICATIONS FOR MUTATION DETECTION STRATEGY
L. Pulkkinen et al., PREDOMINANCE OF THE RECURRENT MUTATION R635X IN THE LAMB3 GENE IN EUROPEAN PATIENTS WITH HERLITZ JUNCTIONAL EPIDERMOLYSIS-BULLOSA HAS IMPLICATIONS FOR MUTATION DETECTION STRATEGY, Journal of investigative dermatology, 109(2), 1997, pp. 232-237
Junctional forms of epidermolysis bullosa (JEB) are characterized by t
issue separation at the level of the lamina lucida, We have recently d
isclosed specific mutations in the LAMA3, LAMB3, and LAMC2 genes encod
ing the subunit polypeptides of the anchoring filament protein laminin
5 in 66 families with different variants of JEB, Examination of the J
EB mutation database revealed recurrence of a particular C-->T substit
ution at nucleotide position 1903 (exon 14) of LAMB3, resulting in the
mutation R635X. The inheritance of this nonsense mutation was noted o
n different genetic backgrounds, suggesting that R635X is a hotspot mu
tation, In this study, we have performed mutation evaluation in a Euro
pean cohort of 14 families with the lethal, Herlitz type of JEB (H-JEB
), The families were first screened for the presence of the R635X muta
tion by restriction enzyme digestion of the PCR product corresponding
to exon 14. Four of the probands were found to be homozygous and six w
ere heterozygous for R635X. The remaining alleles were subjected to mu
tation screening by PCR amplification of individual exons of LAMB3 and
LAMC2, followed by heteroduplex analysis and nucleotide sequencing, I
n three families (six alleles), mutations in LAMC2 were disclosed, In
the remaining eight alleles, additional pathogenetic LAMB3 mutations w
ere found, None of the patients had LAMA3 mutation, Thus, LAMB3 mutati
ons accounted for 22 of 28 JEB alleles (79%), and a total of 14 of 22
LAMB3 alleles (64%) harbored the R635X mutation, signifying its preval
ence as a predominant genetic lesion underlying H-JEB in this European
cohort of patients, This recurrent mutation will facilitate screening
of additional JEB patients for the purpose of prenatal testing of fet
uses at risk for recurrence.