caa a22 4500 397574746 CHVBK 20180308164852.0 cr unu---uuuuu 161202e199602 xx s 000 0 eng 10.1093/hmg/5.2.231 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.2.231 Mutational Hotspots in the LAMB3 Gene in the Lethal (Herlitz) Type of Junctional Epidermolysis Bullosa [Elektronische Daten] [Sirpa Kivirikko, John A. McGrath, Leena Pulkkinen, Jouni Uitto, Angela M. 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. © 1996 Oxford University Press Kivirikko Sirpa Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut McGrath John A. Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut Pulkkinen Leena Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut Uitto Jouni Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut Christiano Angela M. Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut Human Molecular Genetics Oxford University Press 5/2(1996-02), 231-237 0964-6906 5:2<231 1996 5 hmg https://doi.org/10.1093/hmg/5.2.231 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.2.231 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kivirikko Sirpa Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut NATIONALLICENCE 700 1- McGrath John A. Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut NATIONALLICENCE 700 1- Pulkkinen Leena Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut NATIONALLICENCE 700 1- Uitto Jouni Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut NATIONALLICENCE 700 1- Christiano Angela M. Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/2(1996-02), 231-237 0964-6906 5:2<231 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford