title: A unique LAMB3 splice-site mutation with founder effect from the Balkans causes lethal epidermolysis bullosa in several European countries.
abstract: BACKGROUND
  We have encountered repeated cases of recessive lethal generalized severe (Herlitz-type) junctional epidermolysis bullosa (JEB gen sev) in infants born to Hungarian Roma parents residing in a small region of Hungary.
  
  
  OBJECTIVE
  To identify the disease-causing mutation and to investigate the genetic background of its unique carrier group.
  
  
  METHODS
  The LAMB3 gene was analysed in peripheral-blood genomic DNA samples, and the pathological consequences of the lethal defect were confirmed by cutaneous LAMB3cDNA sequencing. A median joining haplotype network within the Y chromosome H1a-M82 haplogroup of individuals from the community was constructed, and LAMB3 single-nucleotide polymorphism (SNP) patterns were also determined.
  
  
  RESULTS
  An unconventional intronic splice-site mutation (LAMB3, c.1133-22G>A) was identified. Thirty of 64 voluntarily screened Roma from the closed community carried the mutation, but none of the 306 Roma from other regions of the country did. The age of the mutation was estimated to be 548 ± 222 years. Within the last year, more patients with JEB gen sev carrying the same unusual mutation have been identified in three unrelated families, all immigrants from the Balkans. Two were compound heterozygous newborns, in Germany and Italy, and one homozygous newborn died in France. Only the French family recognized their Roma background. LAMB3SNP haplotyping confirmed the link between the apparently unrelated Hungarian, German and Italian male cases, but could not verify the same background in the female newborn from France.
  
  
  CONCLUSIONS
  The estimated age of the mutation corresponds to the time period when Roma were wandering in the Balkans.
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Mayer
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary.
authors.forename: P
authors.initials: P
authors.lastname: Silló
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary.
authors.forename: M
authors.initials: M
authors.lastname: Mazán
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Pintér
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary.
authors.forename: M
authors.initials: M
authors.lastname: Medvecz
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Has
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Castiglia
authors.affiliation: Clinical Genetics Department, Jeanne de Flandre Hospital, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Petit
authors.affiliation: French Centre for Hereditary Epidermolysis Bullosa, Archet 2 Hospital, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Charlesworth
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary.
authors.forename: Zs
authors.initials: Z
authors.lastname: Hatvani
authors.affiliation: Institute of Forensic Medicine, Network of Forensic Science Institutes, Ministry of Justice, Budapest, Hungary.
authors.forename: H
authors.initials: H
authors.lastname: Pamjav
authors.affiliation: Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Mária u. 41, 1085, Budapest, Hungary. skarpati@t-online.hu.
authors.forename: S
authors.initials: S
authors.lastname: Kárpáti
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004641:Emigration and Immigration; D016109:Epidermolysis Bullosa, Junctional / Q000208:ethnology / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005602:France / Q000208:ethnology; D015894:Genome, Human; D005858:Germany / Q000208:ethnology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006814:Hungary / Q000208:ethnology; D007223:Infant; D007558:Italy / Q000208:ethnology; D008297:Male; D009154:Mutation / Q000235:genetics*; D058974:Phylogeography; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012313:RNA / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D006178:Romani People / Q000235:genetics*; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D012313:RNA; D022821:RNA Splice Sites; D000097794:Kalinin