Characterization of TGM1 c.984+1G>A mutation identified in a homozygous carrier of lamellar ichthyosis.

[lamellar ichthyosis]

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 (TGase 1 ) deficiency resulting from mutations in both copies of the transglutaminase 1 (TGM 1 ) gene in chromosome 14 .W e report a patient with a severe LI phenotype who has a homozygous putative splicing mutation in the TGM 1 gene . Our aim is to assess the pathologic effect of the TGM 1 c .984 +1 G >A by splicing assays and bioinformatic tools .c .984 +1 G >A mutation created two alternative TGM 1 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 .Met 329 _Val 330 ins 10 ) at the catalytic core domain of TGM 1 protein (codons 247 -572 ), whereas the transcript with the insertion of 32 nucleotides is predicted to encode a truncated protein (p .Val 330 MetfsX 12 ).Our splicing assay , together with bioinformatic prediction tools , supports the pathological effect of the recently identified c .984 +1 G >A mutation in the TGM 1 gene and unravels the molecular mechanism by which c .984 +1 G >A acts .