title: The G2028R glycine substitution mutation in COL7A1 leads to marked inter-familiar clinical heterogeneity in dominant dystrophic epidermolysis bullosa.
abstract: BACKGROUND
  Glycine substitution mutations in COL7A1 not only cause dominant dystrophic epidermolysis bullosa (DDEB), but can also be silent mutations which lead to recessive dystrophic epidermolysis bullosa (RDEB) in combination with additional mutations in the other allele.
  
  
  OBJECTIVE
  In this study, we have examined a large American Caucasian pedigree in which 10 family members from four generations presented with simple toenail dystrophy without skin fragility in autosomal dominant manner.
  
  
  METHODS
  We sequenced COL7A1 of this pedigree.
  
  
  RESULTS
  Mutational analysis indeed detected a heterozygous G-to-A transition at nucleotide position 6082 leading to G2028R in all the affected members. Surprisingly, mutation database revealed that this G2028R mutation had been previously identified in two distinct Asian families with DDEB showing apparent skin fragility and blister formation. One case was a 17-month-old Chinese female with classical phenotype of DDEB and the other was a 27-year-old Japanese female with typical epidermolysis bullosa (EB) pruriginosa. To better understand the molecular mechanisms of this marked inter-familiar clinical heterogeneity, we examined the entire sequence of all the exons and exon-intron borders as well as the promoter region of COL7A1 in all the three families. Sequence results demonstrated no significant nucleotide difference in COL7A1 among the three pedigrees.
  
  
  CONCLUSIONS
  This paper has demonstrated for the first time that identical COL7A1 glycine substitutions can cause remarkably heterogeneous clinical phenotypes extending from simple toe nail dystrophy without skin fragility to typical DDEB and EB pruriginosa. In addition, the fact of inter-familiar, not intra-familiar clinical heterogeneity associated with G2028R suggest that the other molecular mechanisms not controlled by COL7A1 coding sequence might be responsible for the clinical heterogeneity.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawamura
authors.forename: Maki
authors.initials: M
authors.lastname: Goto
authors.forename: Kazuko C
authors.initials: KC
authors.lastname: Sato-Matsumura
authors.forename: Jeffrey
authors.initials: J
authors.lastname: LaDuca
authors.forename: Julia Yu-Yun
authors.initials: JY
authors.lastname: Lee
authors.forename: Takuji
authors.initials: T
authors.lastname: Masunaga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D024143:Collagen Type VII / Q000235:genetics*; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics*; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype
chemical_list: D024143:Collagen Type VII; D005998:Glycine