Combination of a Novel Frameshift Mutation (1929delCA) and a Recurrent Nonsense Mutation (W610X) of the LAMB3 Gene in a Japanese Patient with Herlitz.

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Combination of a Novel Frameshift Mutation (1929delCA) and a Recurrent Nonsense Mutation (W610X) of the LAMB3 Gene in a Japanese Patient with Herlitz Junctional Epidermolysis Bullosa, and their Application for Prenatal Testing Yasuko Takizawa, Hiroshi Shimizu, Leena Pulkkinen, Kaoru Suzumori, Hiroaki Kakinuma, Jouni Uitto, Takeji Nishikawa Journal of Investigative Dermatology Volume 111, Issue 6, Pages 1239-1241 (December 1998) DOI: 10.1038/sj.jid.5600370 Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Identification and verification of the paternal frameshift mutation 1929delCA. (a) The pedigree of the nuclear family (top) and the results of heteroduplex analysis of the PCR products spanning exon 14 of the LAMB3 gene (bottom). The following primers were used for amplification of exon 14: the sense primer, 5'-GCTGCGACTTCTGTTATTCT-3'; the anti-sense primer, 5'-AAATGTAAGGAAGGACCAGC-3'. The PCR products were screened for potential nucleotide substitutions by heteroduplex analysis using conformation-sensitive gel electrophoresis (Ganguly et al. 1993). DNA sequencing was carried out with an automatic sequencer (Genetic Analyzer 310 A; Perkin Elmer ABI, Foster City, CA). Slower migrating bands were observed with DNA from the father (lane F), the older brother (lane 1), and the abortus (lane 3) when compared with the DNA of the control (lane C) and that of the mother (lane M). (b) Direct sequence analysis of the exon 14 in the abortus revealed a heterozygous 2 bp (CA) deletion at nucleotide position 1929 in LAMB3 gene when compared with the normal sequence shown below. (c) The presence of the mutation was verified by restriction enzyme digestion. The mutation abolished a recognition site for MaeIII restriction enzyme. In the case of the normal allele, the 593 bp fragment was digested to 244 bp, 135 bp, 132 bp, and 82 bp fragments, whereas in the case of the mutant allele, a 379 bp fragment resisted digestion in the PCR products of the father (lane F), the older brother (lane 1), and the abortus (lane 3). Journal of Investigative Dermatology 1998 111, 1239-1241DOI: (10.1038/sj.jid.5600370) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Identification and verification of the maternal nonsense mutation W610X. (a) The pedigree of the family. (b) Direct sequencing of the exon 14 of the aborted fetus revealed a heterozygous Gâ†’A transition at nucleotide position 1828 (W610X mutation) (arrow). (c) The presence of the mutation was verified by restriction enzyme digestion. The mutation created a new recognition site for BclI restriction enzyme. Digestion of the mother's (lane M) and the aborted fetus' (lane 3) DNA fragmented the mutant allele to 360 bp and 233 bp bands, whereas the normal allele resisted digestion, indicating heterozygosity for the mutation (top). The mutation also abolished a restriction endonuclease site for Van91I restriction enzyme. In the case of the normal allele, the 593 bp fragment was digested to 358 bp and 235 bp fragments, whereas in the case of the mutant allele, the 593 bp fragment resisted digestion. The PCR product from the father (lane F), the older brother (lane 1), and the unaffected fetus (lane 4) was not digested by BclI but was fragmented by Van91I, similar to the normal control (lane C) (bottom). Journal of Investigative Dermatology 1998 111, 1239-1241DOI: (10.1038/sj.jid.5600370) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions