title: Characterization of TGM1 c.984+1G>A mutation identified in a homozygous carrier of lamellar ichthyosis.
abstract: BACKGROUND
  Autosomal recessive congenital ichthyosis (ARCI) is a rare, nonsyndromic, heterogeneous disorder of cornification. It is divided into three clinical subtypes: lamellar ichthyosis (LI); congenital ichthyosiform erythroderma; and harlequin ichthyosis. In the majority of patients, LI is caused by transglutaminase-1 (TGase1) deficiency resulting from mutations in both copies of the transglutaminase 1 (TGM1) gene in chromosome 14.
  
  
  METHODS
  We report a patient with a severe LI phenotype who has a homozygous putative splicing mutation in the TGM1 gene. Our aim is to assess the pathologic effect of the TGM1 c.984+1G>A by splicing assays and bioinformatic tools.
  
  
  RESULTS
  c.984+1G>A mutation created two alternative TGM1 mRNA splice variants that included 30 or 32 nucleotides of the 5' of intron 6. At the protein level, the partial in-frame aberrant transcript retaining 30 bp of intron 6 led to the insertion of 10 amino acids (p.Met329_Val330ins10) at the catalytic core domain of TGM1 protein (codons 247-572), whereas the transcript with the insertion of 32 nucleotides is predicted to encode a truncated protein (p.Val330MetfsX12).
  
  
  CONCLUSIONS
  Our splicing assay, together with bioinformatic prediction tools, supports the pathological effect of the recently identified c.984+1G>A mutation in the TGM1 gene and unravels the molecular mechanism by which c.984+1G>A acts.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Fachal
authors.forename: Laura
authors.initials: L
authors.lastname: Rodríguez-Pazos
authors.forename: Manuel
authors.initials: M
authors.lastname: Ginarte
authors.forename: Andrés
authors.initials: A
authors.lastname: Beiras
authors.forename: José M
authors.initials: JM
authors.lastname: Suárez-Peñaranda
authors.forename: Jaime
authors.initials: J
authors.lastname: Toribio
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
mesh_terms: D002353:Carrier State; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics*; D009154:Mutation; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics*
chemical_list: D011503:Transglutaminases; C105804:transglutaminase 1